Matrix metalloproteinase (mmp) inhibitors and methods of use thereof

ABSTRACT

Hydantoin based compounds useful as inhibitors of matrix metalloproteinases (MMPs), particularly macrophage elastase (MMP-12) are described. Also described are related compositions and methods of using the compounds to inhibit MMP-12 and treat diseases mediated by MMP-12, such as asthma, chronic obstructive pulmonary disease (COPD), emphysema, acute lung injury, idiopathic pulmonary fibrosis (IPF), sarcoidosis, systemic sclerosis, liver fibrosis, nonalcoholic steatohepatitis (NASH), arthritis, cancer, heart disease, inflammatory bowel disease (IBD), acute kidney injury (AKI), chronic kidney disease (CKD), Alport syndrome, and nephritis.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.17/055,459 filed Nov. 13, 2020, which is a 371 of InternationalApplication No. PCT/US2019/032127 filed May 14, 2019, published Nov. 21,2019 under publication No. WO 2019/222154, which application claimspriority to U.S. Provisional Patent Application No. 62/671,753, filedMay 15, 2018, the disclosures of which are incorporated herein byreference.

BACKGROUND OF THE INVENTION

Matrix metalloproteinases (MMPs) are a superfamily of proteinase enzymesthat are important for the degradation of most extracellular matrixproteins during organogenesis, growth, and normal tissue turnover. MMPsare also believed to be important in the uncontrolled breakdown ofconnective tissue, which relates to a few disease processes such asrheumatoid arthritis, osteoarthritis, gastric ulceration, asthma,emphysema, and tumor metastasis. Therefore, inhibition of one or moreMMPs may be of benefit in these diseases.

Human macrophage elastase (MMP-12) is a particular MMP. MMP-12 exhibitsall the characteristics of other MMPs, but is preferentially producedfrom macrophages infiltrating into tissues where injury or remodeling isoccurring, and degrades extracellular matrix. For example, increasedlevels of MMP-12 have been observed during the onset of emphysema.Additionally, an MMP-12 knock-out mouse model showed no development ofemphysema after being exposed for a lengthy period of time to cigarettesmoke (Hautamkai et al. Science, 1997, 277: 2002-2004). These datasuggest that MMP-12 plays a role in disease progression of emphysema.The involvement of MMP-12 in the development of chronic asthma has alsobeen suggested based on studies in an MMP-12 deficient model of asthma(Warner et al. Am J Pathol. 2004; 165(6): 1921-1930). In the Fas-inducedmodel of acute lung injury, MMP12-deficient mice are protected fromdeveloping pulmonary fibrosis (Matute-Bello et al., Am J Respir Cell MolBiol. 2007; 37(2): 210-221). In a model of pulmonary and hepaticfibrosis induced by Schistosoma mansoni infection, MMP-12 hasprofibrotic activities in the lung and liver (Madala et al. J Immunol2010; 184:3955-3963). MMP-12 may also contribute to Idiopathic pulmonaryfibrosis (IPF) pathogenesis by cleaving extracellular matrix (ECM)proteins, as BALF levels of a type IV collagen fragment generated byMMP-12 are increased in patients with IPF (Sand et al. PLoS One 2013;8:e84934), and human MMP-12 can cleave a number of human ECM proteins invitro (Owen etal. J Leukoc Biol 1999; 65:137-150). Together, theseresults suggest that inhibitors of MMP-12 may be useful in the treatmentof pulmonary diseases, such as chronic obstructive pulmonary disease(COPD), emphysema, asthma, acute lung injury, idiopathic pulmonaryfibrosis (IPF), liver fibrosis and nonalcoholic steatohepatitis (NASH).

MMP-12 has been shown to be secreted from alveolar macrophages ofsmokers (Shapiro et al., Journal of Biological Chemistry, 1993, 268:23824), in foam cells in atherosclerotic lesions (Matsumoto et al., Am.J. Pathol., 1998, 153: 109), and in a nephritis rat model (Kaneko etal., J. Immunol., 2003, 170:3377). MMP-12 also plays a role in coronaryartery disease (Jormsjo et al., Circulation Research, 2000, 86: 998).MMP-12 was also shown to be upregulated in inflammatory bowel disease(IBD) patients as well as in a T-cell mediated model of colitis andcontribute to epithelial degradation and MMP-12−/− mice were protectedagainst TNBS induced colitis (Pender et al., Ann NY Acad Sci. 2006,1072:386-8.). Epithelial and stromal MMP-12 along with MMP-3 and -7 havebeen also upregulated in pouch mucosa of pediatric onset UC, suggestingthat the expression of MMPs pediatric UC pouch in the long-term sharescharacteristics with IBD (Mäkitalo et al., World J Gastroenterol. 2012,18(30):4028-36). Taken together, these observations suggest that MMP-12could be a target for treatment of these diseases.

In view of the involvement of MMP-12 in a number of diseases, attemptshave been made to prepare inhibitors of MMP-12. A number of MMP-12inhibitors are known (see e.g., International Patent ApplicationPublication WO 00/40577; European Patent Application Publication EP 1288 199 A1; U.S. Pat. No. 6,352,9761, and U.S. Patent ApplicationPublication No. 2004/0072871; and European Patent ApplicationPublication EP1394159).

A particular class of MMP inhibitors that have been described are thehydantoin derivatives. For example, International Patent ApplicationPublication WO 02/096426 describes hydantoin derivatives of the generalformula:

which are disclosed as being active as MMP inhibitors, particularlyagainst tumor necrosis factor-alpha converting enzyme (TACE) andaggrecanase. A feature of the disclosed structures of these derivativesis a spiro-linkage between the hydantoin ring and its side chain. U.S.Patent Application Publication No. 2004/0067996 and International PatentApplication Publication WO 2004/108086 describe similar hydantoinderivatives of the general formula:

which are also described as MMP inhibitors, particularly for TACE andaggrecanase.

International Patent Application Publication WO 02/074752 describes thesynthesis of MMP inhibitors and International Patent ApplicationPublication WO 2004/020415 discloses MMP-12 inhibitors, which arehydantoin derivatives of the general formula:

respectively. Some of the disclosed compounds showed MMP inhibitoryactivities, including MMP-12 inhibitory activity.

More recently, inhibitors of MMP-12 have been described in U.S. Pat. No.7,179,831, which are hydantoin derivatives of the general formula:

Hydantoin derivatives are a useful class of MMP inhibitors. However,there is a need in the art to identify hydantoin derivatives havingimproved specificity, potency, and pharmacological properties.

BRIEF SUMMARY OF THE INVENTION

The application satisfies this need by providing hydantoin derivativeshaving high activity and specificity for MMPs, particularly macrophageelastase (MMP-12).

In a general aspect, the application relates to a compound of formula(I-b):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof, wherein:

-   -   ring B is an optionally substituted aryl or optionally        substituted heteroaryl;    -   ring C is an optionally substituted aryl or optionally        substituted heteoraryl;    -   ring D is an optionally substituted aryl or optionally        substituted heteroaryl;    -   each of X, Y and Z is independently selected from the group        consisting of CH₂, O, NR_(x) and S(O)_(q), wherein R_(x) is        hydrogen or alkyl;    -   R₁ is hydrogen or alkyl;    -   R₄ is hydrogen or alkyl;    -   R₅ is hydrogen; and    -   q is 0, 1, or 2,    -   provided that ring B is not furanyl.

In an embodiment, the application relates to a compound of formula (I):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof,wherein:

-   -   ring B is an optionally substituted aryl or optionally        substituted heteroaryl;    -   ring C is aryl or heteoraryl;    -   ring D is aryl or heteroaryl;    -   each of X, Y and Z is independently selected from the group        consisting of CH₂, O, NR_(x) and S(O)_(q), wherein R_(x) is        hydrogen or alkyl;    -   R₁ is hydrogen or alkyl;    -   each R₂ is independently selected from the group consisting of        hydrogen, alkyl, halogen, hydroxyl, haloalkyl, alkoxy,        alkylthio, amine, amide, alkylamine, aminoalkyl, cyano,        hydroxyalkyl, —(CH₂)_(p)C(O)OR₆, and —(CH₂)_(p)OC(O)R₆;    -   each R₃ is independently selected from the group consisting of        hydrogen, alkyl and halo;    -   R₄ is hydrogen or alkyl;    -   R₅ is hydrogen;    -   each R₆ is independently selected from the group consisting of        hydrogen and alkyl, wherein the alkyl is unsubstituted or        substituted with one or more groups independently selected from        the group consisting of amine, hydroxyl, halogen, and alkoxy;    -   m is 1, 2, 3, or 4;    -   n is 1, 2, 3, 4, or 5;    -   p is 0, 1, 2, 3, 4, or 5; and    -   q is 0, 1, or 2,    -   provided that ring B is not furanyl.

In an embodiment, the application relates to a compound of formula (I),or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof, wherein ring C is phenyl.

In an embodiment, the application relates to a compound of formula (I),or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof, wherein ring D is pyridnyl or phenyl.

In an embodiment, the application relates to a compound of formula (I),or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof, wherein ring D is:

In an embodiment, the application relates to a compound of formula (I),or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof, wherein each of R₁, R₄ and R₅ is hydrogen.

In an embodiment, the application relates to a compound of formula (I),or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof, wherein X is S; Y is O; and Z is CH₂.

In an embodiment, the application relates to a compound of formula (I),or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof, wherein ring B is a five or six membered monocyclicheteroaryl having 1-2 heteroatoms independently selected from N, S, andO, wherein the five or six membered monocyclic heteroaryl is optionallysubstituted with —CH₃.

In an embodiment, the application relates to a compound of formula (I),or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof, wherein ring B is pyridinyl, thiophenyl, imidazolyl,pyrazolyl, or oxazolyl, wherein each of pyridinyl, thiophenyl,imidazolyl, pyrazolyl, and oxazolyl is optionally substituted with —CH₃.

In an embodiment, the application relates to a compound of formula (I),or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof, wherein ring B is pyridinyl.

In an embodiment, the application relates to a compound selected fromthe group consisting of a compound of formula (II-a), a compound offormula (II-b), a compound of formula (II-c), and a compound of formula(II-d).

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof,wherein:

-   -   R₁ is hydrogen, —CH₃, or —CH₂CH₃;    -   R₄ is hydrogen or —CH₃;    -   R₅ is hydrogen or —CH₃;    -   R₃ is hydrogen, —F, —Cl, or CH₃;    -   X is S, SO, or SO₂;    -   Y is O, NH, CH₂, or NHCH₃;    -   ring D is pyridinyl or phenyl;    -   R₂ is —CH₃, —CH₂OH, —OH, CH₂OC(O)CH(NH₂)CH(CH₃)₂, —COOH,        —C(O)NH₂, —C(O)NHCH₃, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂, or        —CH₂CH(CH₃)₂; and    -   n is 0 or 1.

In an embodiment, the application relates to a compound of formula (I),or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof, wherein ring B is thiophenyl.

In an embodiment, the application relates to a compound of formula (IV):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof,wherein:

-   -   each of R₁, R₄ and R₅ is hydrogen;    -   X is S;    -   Y is O;    -   R₃ is hydrogen;    -   ring D is phenyl or pyridinyl;    -   R₂ is —CH₃, —C(O)NH₂, —CH₂OH, —OCH₃, or —OH; and    -   n is 0 or 1.

In an embodiment, the application relates to a compound selected fromthe group consisting of a compound of formula (Va), a compound offormula (Vb) and a compound of formula (VI):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof,

wherein:

-   -   R₁ is hydrogen, —CH₃, or —CH₂CH₃;    -   R₄ is hydrogen or —CH₃;    -   R₅ is hydrogen or —CH₃;    -   R₃ is hydrogen, —F, —Cl, or CH₃;    -   X is S, SO, or SO₂;    -   Y is O, NH, CH₂, or NHCH₃;    -   ring D is pyridinyl or phenyl;    -   R₂ is —CH₃, —CH₂OH, —OH, CH₂OC(O)CH(NH₂)CH(CH₃)₂, —COOH,        —C(O)NH₂, —C(O)NHCH₃, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂, or        —CH₂CH(CH₃)₂; and    -   n is 0 or 1.

In an embodiment, the application relates to a compound selected fromthe group consisting of a compound of formula (VII-a) and a compound offormula (VII-b):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof,

wherein:

-   -   each of R₁, R₃, R₄, and R₅ is hydrogen;    -   X is S;    -   Y is O;    -   ring D is phenyl or pyridinyl;    -   R₂ is —CH₃, —C(O)NH₂, —CH₂OH, —OCH₃, or —OH; and    -   n is 0 or 1.

In an embodiment, the application relates to a compound of formula(I-a):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof,

wherein:

-   -   ring B is pyridinyl;    -   Q is CH or N;    -   R₁ is hydrogen, —CH₃, or —CH₂CH₃;    -   R₄ is hydrogen or —CH₃;    -   R₅ is hydrogen or —CH₃;    -   R₂ is selected from the group consisting of —CH₃, —C(O)NH₂,        —CH₂OH, —OCH₃, or —OH;    -   X is S; and    -   Y is O.

In an embodiment, the application relates to a compound selected fromthe group consisting of the compounds listed in Table 1, or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof.

In an embodiment, the application relates to a compound selected fromthe group consisting of the compounds listed in Table 1, orpharmaceutically acceptable salt thereof.

In another general aspect, the application relates to a pharmaceuticalcomposition comprising a compound of the application as describedherein, or a tautomer, stereoisomer, pharmaceutically acceptable salt,or solvate thereof, and at least one pharmaceutically acceptablecarrier.

Other general aspects of the application relate to methods of inhibitingmacrophage elastase (MMP-12) in a subject in need thereof, and methodsof treating a disease mediated by macrophage elastase (MMP-12) in asubject in need thereof.

In an embodiment, the application relates to a method of inhibitingmacrophage elastase (MMP-12) in a subject in need thereof, comprisingadministering to the subject a compound or pharmaceutical composition ofthe application.

In an embodiment, the application relates to a method of treating adisease mediated by macrophage elastase (MMP-12) in a subject in needthereof, comprising administering to the subject a compound orpharmaceutical composition of the application.

In some embodiments, the disease is selected from the group consistingof asthma, chronic obstructive pulmonary disease (COPD), emphysema,acute lung injury, and idiopathic pulmonary fibrosis (IPF), sarcoidosis,systemic sclerosis, liver fibrosis, nonalcoholic steatohepatitis (NASH),arthritis, cancer, heart disease, Inflammatory bowel disease (IBD),acute kidney injury (AKI), chronic kidney disease (CKD), Alportsyndrome, and nephritis.

Also provided herein is a compound of the application or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof, or acomposition of the application for use in a method of inhibitingmacrophage elastase (MMP-12), or treating a disease mediated bymacrophage elastase (MMP-12). In some embodiments, the disease isselected from the group consisting of asthma, chronic obstructivepulmonary disease (COPD), emphysema, acute lung injury, and idiopathicpulmonary fibrosis (IPF), sarcoidosis, systemic sclerosis, liverfibrosis, nonalcoholic steatohepatitis (NASH), arthritis, cancer, heartdisease, Inflammatory bowel disease (IBD), acute kidney injury (AKI),chronic kidney disease (CKD), Alport syndrome, and nephritis.

Also provided herein is use of a compound of the application or atautomer, stereoisomer, pharmaceutically acceptable salt, or solvatethereof, or a composition of the application in the manufacture of amedicament for inhibiting macrophage elastase (MMP-12) or treating adisease mediated by macrophage elastase (MMP-12). Preferably, thedisease is selected from the group consisting of asthma, chronicobstructive pulmonary disease (COPD), emphysema, acute lung injury, andidiopathic pulmonary fibrosis (IPF), sarcoidosis, systemic sclerosis,liver fibrosis, nonalcoholic steatohepatitis (NASH), arthritis, cancer,heart disease, Inflammatory bowel disease (IBD), acute kidney injury(AKI), chronic kidney disease (CKD), Alport syndrome, and nephritis.

In yet another general aspect, the application relates to a method ofpreparing a pharmaceutical composition of the application, comprisingcombining a compound of the application, or a tautomer, stereoisomer,pharmaceutically acceptable salt, or solvate thereof, and at least onepharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE FIGURES

The foregoing summary, as well as the following detailed description ofthe invention, will be better understood when read in conjunction withthe appended figures. It should be understood that the invention is notlimited to the precise embodiments shown in the drawings.

In the figures:

FIGS. 1A-1H depict the results of the efficacy study of MMP-12inhibitors on SD rat kidney fibrosis model by unilateral ureteralocclusion (UUO) described in Example 3; FIG. 1A shows changes in serumBUN at 2 weeks as compared to pre-operation (pre-OP) for each of theexperimental SD rat groups; FIG. 1B shows changes in serum creatine at 2weeks as compared to pre-operation (pre-OP) for each of the experimentalSD rat groups; FIG. 1C shows histology images of kidneys from H&Estaining at ×200 magnification; panel A: right kidney as normal control,panel B: vehicle treated animals, panel C: PC-16 treated animals (2mg/kg/day), panel D: PC-16 treated animals (6 mg/kg/day), panel E: PC-16treated animals (20 mg/kg/day); FIG. 1D shows the renal tubular damagescore (I) and the renal interstitial inflammatory score (II) for each ofthe experimental SD rat groups; T-test in (I): ***p<0.05 vs. model,$p<0.05 vs. PC-16 (2 mg/kg/day), $$p<0.01 vs. PC-16 (6 mg/kg/day);T-test in (II): **p<0.05 vs. model, ***p<0.001 vs. model, FIG. 1E showshistology images in the kidneys from Masson Trichrome staining at amagnification of ×200; panels A-E correspond to panels A-E as describedin FIG. 1C; FIG. 1F shows the interstitial fibrosis score for kidneyinterstitial fibrosis in the cortex; T-test: **p<0.01 vs. model,***p<0.001 vs. model, $p<0.05 vs. PC-16 (2 mg/kg/day), $$p<0.01 vs.PC-16 (2 mg/kg/day); FIG. 1G shows collagen I deposition (I) andcollagen IV deposition (II) in the cortex area of the left kidney by IHCstaining at ×200 magnification; panels A-E correspond to panels A-E asdescribed in FIG. 1C; FIG. 1H shows collagen I deposition positivestaining (%) (I) and collagen IV deposition positive staining (%) (II)in the cortex area of the left kidney as determined from the IHCstaining in FIG. 1G; One-way ANOVA: ***p<0.001 vs. normal control;T-test: #p<0.05 vs. model.

DETAILED DESCRIPTION OF THE INVENTION

Various publications, articles and patents are cited or described in thebackground and throughout the specification; each of these references isherein incorporated by reference in its entirety. Discussion ofdocuments, acts, materials, devices, articles or the like which has beenincluded in the present specification is for the purpose of providingcontext for the invention. Such discussion is not an admission that anyor all of these matters form part of the prior art with respect to anyinventions disclosed or claimed.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood to one of ordinary skill inthe art to which this invention pertains. Otherwise, certain terms usedherein have the meanings as set forth in the specification. All patents,published patent applications and publications cited herein areincorporated by reference as if set forth fully herein.

It must be noted that as used herein and in the appended claims, thesingular forms “a,” “an,” and “the” include plural reference unless thecontext clearly dictates otherwise.

Unless otherwise indicated, the term “at least” preceding a series ofelements is to be understood to refer to every element in the series.Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the invention.

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising”, will be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integer or step. Whenused herein the term “comprising” can be substituted with the term“containing” or “including” or sometimes when used herein with the term“having”.

When used herein “consisting of” excludes any element, step, oringredient not specified in the claim element. When used herein,“consisting essentially of” does not exclude materials or steps that donot materially affect the basic and novel characteristics of the claim.Any of the aforementioned terms of “comprising”, “containing”,“including”, and “having”, whenever used herein in the context of anaspect or embodiment of the application can be replaced with the term“consisting of” or “consisting essentially of” to vary scopes of thedisclosure.

As used herein, the conjunctive term “and/or” between multiple recitedelements is understood as encompassing both individual and combinedoptions. For instance, where two elements are conjoined by “and/or,” afirst option refers to the applicability of the first element withoutthe second. A second option refers to the applicability of the secondelement without the first. A third option refers to the applicability ofthe first and second elements together. Any one of these options isunderstood to fall within the meaning, and therefore satisfy therequirement of the term “and/or” as used herein. Concurrentapplicability of more than one of the options is also understood to fallwithin the meaning, and therefore satisfy the requirement of the term“and/or.”

Unless otherwise stated, any numerical value, such as a concentration ora concentration range described herein, are to be understood as beingmodified in all instances by the term “about.” Thus, a numerical valuetypically includes +10% of the recited value. For example, therecitation of “10-fold” includes 9-fold and 11-fold. As used herein, theuse of a numerical range expressly includes all possible subranges, allindividual numerical values within that range, including integers withinsuch ranges and fractions of the values unless the context clearlyindicates otherwise.

As used herein, “subject” means any animal, preferably a mammal, mostpreferably a human, to whom will be or has been treated by a methodaccording to an embodiment of the application. The term “mammal” as usedherein, encompasses any mammal. Examples of mammals include, but are notlimited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits,guinea pigs, non-human primates (NHPs) such as monkeys or apes, humans,etc., more preferably a human.

The phrase “pharmaceutically acceptable salt(s)”, as used herein, meansthose salts of a compound of interest that are safe and effective fortopical use in mammals and that possess the desired biological activity.Pharmaceutically acceptable salts include salts of acidic or basicgroups present in the specified compounds. Pharmaceutically acceptableacid addition salts include, but are not limited to, hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, isonicotinate, carbonate, bicarbonate, acetate, lactate,salicylate, citrate, tartrate, propionate, butyrate, pyruvate, oxalate,malonate, pantothenate, bitartrate, ascorbate, succinate, maleate,gentisinate, fumarate, gluconate, glucaronate, saccharate, formate,benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate,p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain compoundsused in the application can form pharmaceutically acceptable salts withvarious amino acids. Suitable base salts include, but are not limitedto, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc,bismuth, and diethanolamine salts. For a review on pharmaceuticallyacceptable salts see Berge et al., 66 J. Pharm. Sci. 1-19 (1977),incorporated herein by reference.

As used herein, the term “alkyl” means a saturated, monovalent,unbranched or branched hydrocarbon chain. An alkyl group can beunsubstituted or substituted with one or more suitable substituents.Examples of alkyl groups include, but are not limited to, methyl (Me),ethyl (Et), propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl,isobutyl, tert-butyl), and pentyl (e.g., n-pentyl, isopentyl,neopentyl), etc. An alkyl group can have a specified number of carbonatoms. When numbers appear in a subscript after the symbol “C”, thesubscript defines with more specificity the number of carbon atoms thata particular alkyl can contain. For example, “C₁ to C₁₀ alkyl” or “C₁₋₁₀alkyl” is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, andC₁₀ alkyl groups. Additionally, for example, “C₁ to C₆ alkyl” or “C₁₋₆alkyl” denotes alkyl having one to six carbon atoms.

The term “alkoxy” as used herein refers to an —O-alkyl group, whereinalkyl is as defined above. An alkoxy group is attached to the parentmolecule through an oxygen atom. An alkoxy group can have a specifiednumber of carbon atoms. For example, “C₁ to C₁₀ alkoxy” or “C₁₋₁₀alkoxy” is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, andC₁₀ alkoxy groups. Additionally, for example, “C₁ to C₆ alkoxy” or “C₁₋₆alkoxy” denotes alkoxy having 1 to 6 carbon atoms. Examples of alkoxyinclude, but are not limited to, methoxy, ethoxy, propoxy (e.g.,n-propoxy, isopropoxy), butoxy (e.g., n-butoxy, isobutoxy, tert-butoxy),pentyloxy (e.g., n-pentyloxy, isopentyloxy, neopentyloxy), etc. Analkoxy group can be unsubstituted or substituted with one or moresuitable substituents. Similarly, “alkylthio” or “thioalkoxy” representsan alkyl group as defined above attached through a sulfur bridge, forexample, —S— methyl, —S-ethyl, etc. Representative examples of alkylthioinclude, but are not limited to, —SCH₃, —SCH₂CH₃, etc.

As used herein, the term “halogen” means fluorine, chlorine, bromine, oriodine. Correspondingly, the term “halo” means fluoro, chloro, bromo,and iodo.

“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups substituted with one or morehalogen atoms. Examples of haloalkyl include, but are not limited to,fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl,2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.

The terms “hydroxy” and “hydroxyl” can be used interchangeably, andrefer to —OH.

The term “carboxy” refers to —COOH.

The term “cyano” refers to —CN.

The term “amino” refers to —NH₂. The term “alkylamino” refers to anamino group in which one or both of the hydrogen atoms attached tonitrogen is substituted with an alkyl group. For example, alkylaminoincludes methylamino (—NHCH₃), dimethylamino (—N(CH₃)₂), —NHCH-₂CH₃,etc.

The term “aminoalkyl” as used herein is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupssubstituted with one or more amino groups. For example, “C₁₋₄aminoalkyl” is intended to include C₁, C₂, C₃, and C₄ alkyl groupssubstituted with one or more amino groups. Representative examples ofaminoalkyl groups include, but are not limited to, —CH₂NH₂, —CH₂CH₂NH₂,and —CH₂CH(NH₂)CH₃.

As used herein, “amide” refers to —C(O)N(R)₂, wherein each R isindependently an alkyl group or a hydrogen. Examples of amides include,but are not limited to, —C(O)NH₂, —C(O)NHCH₃, and —C(O)N(CH₃)₂.

The terms “hydroxylalkyl” and “hydroxyalkyl” are used interchangeably,and refer to an alkyl group substituted with one or more hydroxylgroups. The alkyl can be a branched or straight-chain aliphatichydrocarbon. Examples of hydroxylalkyl include, but are not limited to,hydroxylmethyl (—CH₂OH), hydroxylethyl (—CH₂CH₂OH), etc.

The term “aryl” as used herein is a group that contains any carbon-basedaromatic group including, but not limited to, phenyl, naphthyl,anthracenyl, phenanthranyl, and the like. Aryl moieties are well knownand described, for example, in Lewis, R. J., ed., Hawley's CondensedChemical Dictionary, 13^(th) Edition, John Wiley & Sons, Inc., New York(1997). An aryl group can be substituted or unsubstituted with one ormore suitable substituents. An aryl group can be a single ring structure(i.e., monocyclic) or comprise multiple ring structures (i.e.,polycyclic) that are fused ring structures. Preferably, an aryl group isa monocyclic aryl group for instance phenyl.

As used herein, the term “heteroaryl” includes stable monocyclic andpolycyclic aromatic hydrocarbons that contain at least one heteroatomring member such as sulfur, oxygen, or nitrogen. Heteroaryl can bemonocyclic or polycyclic, e.g., bicyclic or tricyclic. Each ring of aheteroaryl group containing a heteroatom can contain one or two oxygenor sulfur atoms and/or from one to four nitrogen atoms provided that thetotal number of heteroatoms in each ring is four or less and each ringhas at least one carbon atom. For bicyclic heteroaryl groups, the fusedrings completing the bicyclic group can contain only carbon atoms andcan be saturated, partially saturated, or unsaturated. Heteroaryl groupswhich are polycyclic, e.g., bicyclic or tricyclic must include at leastone fully aromatic ring but the other fused ring or rings can bearomatic or non-aromatic. The heteroaryl group can be attached at anyavailable nitrogen or carbon atom of any ring of the heteroaryl group.Preferably, the term “heteroaryl” refers to 5- or 6-membered monocyclicgroups and 9- or 10-membered bicyclic groups which have at least oneheteroatom (O, S, or N) in at least one of the rings, wherein theheteroatom-containing ring preferably has 1, 2, or 3 heteroatoms, morepreferably 1 or 2 heteroatoms, selected from O, S, and/or N. Aheteroaryl group can be unsubstituted, or substituted with one or moresuitable substituents. The nitrogen heteroatom(s) of a heteroaryl can besubstituted or unsubstituted. The nitrogen and sulfur heteroatom(s) of aheteroaryl can optionally be oxidized (i.e., N→O and S(O)_(r), wherein ris 0, 1 or 2).

Exemplary monocyclic heteroaryl groups include, but are not limited to,pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thiophenyl, oxadiazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl. Exemplarybicyclic heteroaryl groups include, but are not limited to, indolyl,benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl,tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl,cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridinyl, furopyridinyl,dihydroisoindolyl, and tetrahydroquinolinyl.

In accordance with convention used in the art:

is used in structural formulas herein to depict the bond that is thepoint of attachment of the moiety or substituent to the core or backbonestructure.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent can be bonded to any atom on thering.

As referred to herein, the term “substituted” means that at least onehydrogen atom is replaced with a non-hydrogen group, provided that allnormal valencies are maintained and that the substitution results in astable compound. When a particular group is “substituted,” that groupcan have one or more substituents, preferably from one to fivesubstituents, more preferably from one to three substituents, mostpreferably from one to two substituents, independently selected from thelist of substituents. The term “independently” when used in reference tosubstituents, means that when more than one of such substituents ispossible, such substituents can be the same or different from eachother. Examples of suitable substituents include, but are not limitedto, alkyl, halogen, alkoxy, amide, alkythio, amine, alkylamine,aminoalkyl, hydroxyalkyl, hydroxyl, carboxyl, etc., such as C₁₋₄ alkyl,C₁₋₃ alkoxy, —OH, —COOH, —F, —Cl, —C(O)NHCH₃, —C(O)N(CH₃)₂.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-3 R groups, then said group canbe optionally substituted with up to three R groups, and at eachoccurrence, R is selected independently from the definition of R.

The terms “optional” or “optionally” mean that the event or circumstancedescribed subsequently can, but need not, occur, and such a descriptionincludes the situation in which the event or circumstance does or doesnot occur. For example, “optionally substituted aryl” means that asubstituent group can be, but need not be, present, and such adescription includes the situation of the aryl group being substitutedby a suitable substituent and the aryl group being not substituted byany substituent.

One skilled in the art will recognize that in certain embodimentscompounds of the application can have one or more asymmetric carbonatoms in their structure. As used herein, any chemical formulas withbonds shown only as solid lines and not as solid wedged or hashed wedgedbonds, or otherwise indicated as having a particular configuration(e.g., R or S) around one or more atoms, contemplates each possiblestereoisomer, or mixture of two or more stereoisomers. In other words,if the stereochemistry of a structure is not specified, the structure isintended to encompass all individual stereoisomers and mixtures thereof.Stereoisomers includes enantiomers and diastereomers. Enantiomers arestereoisomers that are non-super-imposable mirror images of each other.A 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture.Diastereomers (or diastereoisomers) are stereoisomers that are notenantiomers, i.e., they are not related as mirror images, and occur whentwo or more stereoisomers of a compound have different configurations atone or more of the equivalent stereocenters and are not mirror images ofeach other. Substituent groups (e.g., alkyl, heterocyclyl, etc.) cancontain stereocenters in either the R or S configuration.

Thus, included within the scope of the invention are thestereochemically pure isomeric forms of the compounds of the invention(i.e., a single enantiomer or a single diastereomer) as well as mixturesthereof including their racemates. When a specific stereoisomer isidentified, this means that the stereoisomer is substantially free,i.e., associated with less than 50%, preferably less than 20%, morepreferably less than 5%, in particular less than 2% and most preferablyless than 1% of the other stereoisomers. For example, when a compound isfor instance specified as (R), this means that the compound issubstantially free of the (S) isomer. Compounds of the applicationdescribed herein can be used as racemic mixtures, enantiomerically ordiastereomerically enriched mixtures, or as enantiomerically ordiastereomerically pure individual stereoisomers.

Stereochemically pure isomeric forms can be obtained by techniques knownin the art in view of the present disclosure. For example,diastereoisomers can be separated by physical separation methods such asfractional crystallization and chromatographic techniques, andenantiomers can be separated from each other by the selectivecrystallization of the diastereomeric salts with optically active acidsor bases or by chiral chromatography. Pure stereoisomers can also beprepared synthetically from appropriate stereochemically pure startingmaterials, or by using stereoselective reactions.

Compounds of the application can also form tautomers. The term“tautomer” refers to compounds that are interchangeable forms of aparticular compound structure and that vary in the displacement ofhydrogen atoms and electrons. Tautomers are constitutional isomers ofchemical compounds that readily interconvert, usually resulting inrelocation of a proton (hydrogen). Thus, two structures can be inequilibrium through the movement of pi electrons and an atom (usuallyhydrogen). All tautomeric forms and mixtures of tautomers of thecompounds of the application are including with the scope of theapplication.

Compounds of the application can exist in solvated and unsolvated forms.The term “solvate” means a physical association, e.g., by hydrogenbonding, of a compound of the application with one or more solventmolecules. The solvent molecules in the solvate can be present in aregular arrangement and/or a non-ordered arrangement. The solvate cancomprise either a stoichiometric or nonstoichiometric amount of thesolvent molecules. “Solvate” encompasses both solution-phase andisolable solvates. Compounds of the application can form solvates withwater (i.e., hydrates) or common organic solvents. Exemplary solvatesinclude, but are not limited to, hydrates, ethanolates, methanolates,and isopropanolates. Methods of solvation are generally known in theart.

Also included within the scope of the application are all isotopes ofatoms occurring in the compounds of the application. Isotopes includethose atoms having the same atomic number but different mass numbers. Byway of general example and without limitation, isotopes of hydrogeninclude deuterium and tritium. Isotopes of carbon include ¹³C and ¹⁴C.Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed.

As used herein, the name of a compound is intended to encompass allpossible existing isomeric forms (e.g., optical isomer, enantiomer,diastereomer, racemate or racemic mixture), tautomers, andpharmaceutically acceptable salts, of the compound.

Compounds

In a general aspect, the application relates to a compound of formula(I-b):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof, wherein:

-   -   ring B is an optionally substituted aryl or optionally        substituted heteroaryl;    -   ring C is an optionally substituted aryl or optionally        substituted heteoraryl;    -   ring D is an optionally substituted aryl or optionally        substituted heteroaryl;    -   each of X, Y and Z is independently selected from the group        consisting of CH₂, O, NR_(x) and S(O)_(q), wherein R_(x) is        hydrogen or alkyl;    -   R₁ is hydrogen or alkyl;    -   R₄ is hydrogen or alkyl;    -   R₅ is hydrogen; and    -   q is 0, 1, or 2,    -   provided that ring B is not furanyl.

In an embodiment, provided is a compound of formula (I):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof,wherein:

-   -   ring B is an optionally substituted aryl or optionally        substituted heteroaryl;    -   ring C is aryl or heteroaryl;    -   ring D is aryl or heteroaryl;    -   each of X, Y and Z is independently selected from the group        consisting of O, CH₂, NR_(x) and S(O)_(q), wherein R_(x) is        hydrogen or alkyl;    -   R₁ is hydrogen or alkyl;    -   each R₂ is independently selected from the group consisting of        hydrogen, alkyl, halo, hydroxyl, haloalkyl, alkoxy, alkylthio,        amino, amide, alkylamino, aminoalkyl, cyano, hydroxyalkyl,        —(CH₂)_(p)C(O)OR₆, and —(CH₂)_(p)OC(O)R₆;    -   each R₃ is independently selected from the group consisting of        hydrogen, alkyl and halo;    -   R₄ is hydrogen or alkyl;    -   R₅ is hydrogen;    -   each R₆ is independently selected from the group consisting of        hydrogen and alkyl, wherein the alkyl is unsubstituted or        substituted with one or more groups independently selected from        the group consisting of amino, hydroxyl, halo, and alkoxy;    -   m is 1, 2, 3, or 4;    -   n is 1, 2, 3, 4, or 5;    -   p is 0, 1, 2, 3, 4, or 5; and    -   q is 0, 1, or 2.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein ring C is optionally substituted aryl, preferably optionallysubstituted phenyl.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein ring C is optionally substituted heteroaryl, preferablyoptionally substituted pyridinyl.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein m is 1, and R₃ is independently hydrogen, alkyl, or halo,preferably hydrogen, —CH₃, —F, or —Cl, more preferably H.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein ring C is phenyl, m is 1, and R₃ is hydrogen.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein ring C is phenyl, m is 1, and R₃ is fluoro.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein ring C is phenyl, m is 1, and R₃ is methyl.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein ring D is an optionally substituted aryl, preferably anoptionally substituted phenyl.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein ring D is an optionally substituted heteroaryl.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein ring D is optionally substituted with 1, 2, 3, 4, or 5substitutent groups, preferably 1 or 2 substituent groups, independentlyselected from the group consisting of alkyl, halo, haloalkyl, alkoxy,alkylthio, amino, amide, alkylamino, aminoalkyl, cyano, hydroxyalkyl,—(CH₂)_(p)C(O)OR₆, and —(CH₂)_(p)OC(O)R₆, wherein p is 0, 1, 2, 3, 4, or5. The substituent group, if present, can be attached at any position ofring D. Preferably, ring D is substituted with one substituent group.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein ring D is a monocyclic aryl or monocyclic heteroaryl groupsubstituted with one substituent at the meta position, preferably phenylor pyridinyl substituted at the meta position, relative to the bond tovariable Z. Particularly preferred substituent groups for ring D includemethyl (—CH₃), amide (—C(O)NH-₂), methoxy (—OCH₃), hydroxyl (—OH), andhydroxylmethyl (—CH₂OH).

In a particular embodiment, ring D is phenyl.

In another particular embodiment ring D is pyridinyl.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein n is 1 and R₂ is C₁₋₃ alkoxy (e.g., —OCH₃, —OCH₂CH₂CH₃,—OCH₂CH₃, —OCH(CH₃)₂), C₁₋₄ alkyl (e.g., —CH₃, —CH₂CH₃, —CH₂CH(CH₃)₂),—CH₂OH, —OH, —COOH, —C(O)NH₂, —C(O)NHCH₃, or —CH₂OC(O)CH(NH₂)CH(CH₃)₂,—C(O)NH₂, —C(O)NHCH₃. Preferably R₂ is —CH₃, —C(O)NH₂, —CH₂OH, —OCH₃, orOH.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein ring D is:

According to embodiments of the application, the chiral carbon atom ofthe hydantoin moiety can be unsubstituted (i.e., R₁ is hydrogen) orsubstituted. When substituted, the R₁ substituent is preferably alkyl.Preferred alkyl groups for substitution of the chiral carbon atom of thehydantoin moiety include C₁₋₂ alkyl groups, such as methyl and ethyl.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein R₁ is hydrogen, —CH₃ or —CH₂CH₃.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein R₁ is hydrogen.

Substitution of the nitrogen atoms of the hydantoin moiety is alsopossible. According to embodiments of the application, R₄ and R₅ areeach independently hydrogen or alkyl. Preferred alkyl groups includemethyl.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein R₄ is hydrogen or —CH₃ and R₅ is —CH₃.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein each of R₄ and R₅ is hydrogen.

According to embodiments of the application, each of X, Y, and Z isindependently selected from the group consisting of O, NR_(x), CH₂, andS(O)_(q), wherein q is 0, 1, or 2 and R_(x) is hydrogen or alkyl. Assuch, each of the linker units X, Y and Z is independently selected fromO, S, S(O), SO₂, NH, N-alkyl, and CH₂. Preferably, each of X, Y, and Zis independently selected from S, S(O), S(O)₂, CH₂, and O, morepreferably S, CH₂, and O.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein X is O, Y is O, and Z is CH₂.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein X is S, Y is S, and Z is CH₂.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein X is O, Y is S, and Z is CH₂.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein X is S, Y is O, and Z is CH₂.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein Z is O, Y is CH₂, and X is S.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein Z is S, Y is CH₂, and XisO.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein X is S(O), Y is O, and Z is CH₂.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein X is S(O)₂, Y is O, and Z is CH₂.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein X is S, Y is NH, and Z is CH₂.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein X is S, Y is N(CH₃), and Z is CH₂.

In a preferred embodiment, provided is a compound of formula (I), or atautomer, stereoisomer, pharmaceutically acceptable salt, or solvatethereof, wherein one of X and Y is S and the other is O.

In a more preferred embodiment, provided is a comound of formula (I) ora tautomer, stereoisomer, pharmaceutically acceptable salt, or solvatethereof, wherein X is S and Y is O.

In another preferred embodiment, provided is a compound of formula (I)or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof, wherein Z is CH₂.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein ring B is an optionally substituted aryl, such as phenyl.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein ring B is an optionally substituted heteroaryl. Preferably, ringB is an optionally substituted 5- or 6-membered heteroaryl having 1-2heteroatoms selected from N, S, and O. In particular embodiments, ring Bis a 5-membered heteroaryl ring, such as imidazolyl, thiophenyl,oxazolyl, or pyrazolyl. In other particular embodiments, ring B is a6-membered heteroaryl, such as pyridinyl or pyridinyl N-oxide. Anypositional or regioisomer of the heteroaryl ring can be used, meaningthat the hydantoin moiety and X linker can be connected to theheteroaryl at any substitutable carbon atom on the heteroaryl ring. Forexample, when ring B is a 5-membered heteroaryl ring containing 1heteroatom, the hydantoin moiety and X linker can be connected to the5-membered heteroaryl ring in a 2, 3-substitution pattern, a 2,4-substitution pattern, a 2, 5-substitution pattern, a 3, 4-substitutionpattern, etc., relative to the heteroatom. As another illustrativeexample, when ring B is a 6-membered heteroaryl ring containing oneheteroatom, the hydantoin moiety and X linker can be connected to the6-membered heteroaryl ring in a 2, 3-substitution pattern, a 2,4-substitution pattern, a 2, 5-substitution pattern, a 2, 6-substitutionpattern, a 3, 4-substitution pattern, etc., relative to the heteroatom.

In some embodiments, provided is a compound of formula (I), or atautomer, stereoisomer, pharmaceutically acceptable salt, or solvatethereof, wherein ring B is substituted. Ring B can be substituted on anysubstitutable carbon atom of an aryl or heteroaryl ring, or anysubstitutable heteroatom, e.g., nitrogen atom, of a heteroaryl ring. Forexample, ring B can be substituted with an alkyl group, e.g., methyl,including substitution with a methyl group for instance on a nitrogenatom of a heteroaryl ring, e.g., imidazolyl or pyrazolyl.

In some embodiments, provided is a compound of formula (I), or atautomer, stereoisomer, pharmaceutically acceptable salt, or solvatethereof, wherein ring B is pyridinyl, pyrazolyl, or imidazolyl, whereineach of the pyridinyl, pyrazolyl, or imidazolyl is optionallysubstituted with —CH₃.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein ring B is pyridinyl optionally substituted with —CH₃.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein ring B is pyridinyl N-oxide.

In some embodiments, wherein ring B is pyridinyl, provided is a compoundof formula (II):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof,wherein each of the variables are as defined above for the compound offormula (I).

In certain embodiments, provided is a compound of formula (II), or atautomer, stereoisomer, pharmaceutically acceptable salt, or solvatethereof, wherein:

-   -   ring C is phenyl or pyridinyl;    -   R₁ is hydrogen, —CH₃ or —CH₂CH₃;    -   R₄ is hydrogen or —CH₃;    -   R₅ is hydrogen or —CH₃;    -   X is S, S(O), or SO₂;    -   R₃ is hydrogen, —CH₃, —F, or —Cl;    -   Y is O, NH, CH₂, or —NH₃;    -   Z is CH₂;    -   ring D is phenyl or pyridinyl; and    -   R₂ is C₁₋₃ alkoxy, C₁₋₄ alkyl, —CH₂OH, —OH, —COOH, —C(O)NH₂,        —C(O)NHCH₃, or —CH₂OC(O)CH(NH₂)CH(CH₃)₂;    -   m is 1; and    -   n is 1.

In particular embodiments, provided is a compound of formula (II-a),(II-b), (II-c), or (II-d):

a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvatethereof, wherein each of the variables are as defined above for thecompound of formula (I) or formula (II).

In certain embodiments, provided is a compound of formula (II-a),(II-b), (II-c), or (II-d), or a tautomer, stereoisomer, pharmaceuticallyacceptable salt, or solvate thereof, wherein:

-   -   R₁ is hydrogen, —CH₃ or —CH₂CH₃;    -   R₄ is hydrogen or —CH₃;    -   R₅ is hydrogen or —CH₃;    -   X is S, S(O), or SO₂;    -   R₃ is hydrogen, —CH₃, —F, or —Cl;    -   Y is O, NH, CH₂, or —NH₃;    -   Z is CH₂;    -   ring D is phenyl or pyridinyl; and    -   R₂ is C₁₋₃ alkoxy, C₁₋₄ alkyl, —CH₂OH, —OH, —COOH, —C(O)NH₂,        —C(O)NHCH₃, or —CH₂OC(O)CH(NH₂)CH(CH₃)₂; and    -   n is 1.

In a preferred embodiment, wherein ring B is pyridinyl, provided is acompound of formula (II-b), or a tautomer, stereoisomer,pharmaceutically acceptable salt, or solvate thereof.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein ring B is thiophenyl.

In some embodiments, wherein ring B is thiophenyl, provided is acompound of formula (IV):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof, wherein each of the variables are as defined above forthe compound of formula (I).

In certain embodiments, provided is a compound of formula (IV), or atautomer, stereoisomer, pharmaceutically acceptable salt, or solvatethereof, wherein:

-   -   each of R₁, R₄, and R₅ is hydrogen;    -   X is S;    -   Y is O;    -   Z is CH₂;    -   R₃ is hydrogen;    -   ring D is phenyl or pyridinyl; and    -   R₂ is —CH₃, —C(O)NH₂, —CH₂OH, —OCH₃, or —OH; and    -   n is 1.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein ring B is imidazolyl.

In some embodiments, wherein ring B is imidazolyl, provided is acompound of formula (Va) or (Vb):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof, wherein each of the variables are as defined above forthe compound of formula (I).

In certain embodiments, provided is a compound of formula (V), or atautomer, stereoisomer, pharmaceutically acceptable salt, or solvatethereof, wherein:

-   -   each of R₁, R₄, and R₅ is hydrogen;    -   X is S;    -   Y is O;    -   Z is CH₂;    -   R₃ is hydrogen;    -   ring D is phenyl or pyridinyl; and    -   R₂ is —CH₃, —C(O)NH₂, —CH₂OH, —OCH₃, or —OH; and    -   n is 1.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein ring B is pyrazolyl.

In some embodiments, wherein ring B is pyrazolyl, provided is a compoundof formula (VI):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof,wherein each of the variables are as defined above for the compound offormula (I).

In certain embodiments, provided is a compound of formula (VI), or atautomer, stereoisomer, pharmaceutically acceptable salt, or solvatethereof, wherein:

-   -   each of R₁, R₄, and R₅ is hydrogen;    -   X is S;    -   Y is O;    -   Z is CH₂;    -   R₃ is hydrogen;    -   ring D is phenyl or pyridinyl; and    -   R₂ is —CH₃, —C(O)NH₂, —CH₂OH, —OCH₃, or —OH; and    -   n is 1.

In an embodiment, provided is a compound of formula (I), or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein ring B is oxazolyl.

In some embodiments, wherein ring B is oxazolyl, provided is a compoundof formula (VII):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof, wherein each of the variables are as defined above forthe compound of formula (I).

In certain embodiments, provided is a compound of formula (VII), or atautomer, stereoisomer, pharmaceutically acceptable salt, or solvatethereof, wherein:

-   -   each of R₁, R₄, and R₅ is hydrogen;    -   X is S;    -   Y is O;    -   Z is CH₂;    -   R₃ is hydrogen;    -   ring D is phenyl or pyridinyl; and    -   R₂ is —CH₃, —C(O)NH₂, —CH₂OH, —OCH₃, or —OH; and    -   n is 1.

In particular embodiments, wherein ring B is oxazolyl, provided is acompound of formula (VII-a) or a compound of formula (VII-b):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof,wherein each of the variables are as defined above for the compound offormula (I) or formula (VII).

Compounds of particular interest include compounds of formula (I-a):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof,wherein Q is CH or N, and the rest of the variable groups are as definedabove for the compound of formula (I).

In an embodiment, provided is a compound of formula (I-a) or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein Q is CH.

In an embodiment, provided is a compound of formula (I-a) or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein Q is N.

In an embodiment, provided is a compound of formula (I-a) or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein R₂ is alkyl, halogen, haloalkyl, alkoxy, alkylthio, amino,amide, alkylamino, aminoalkyl, cyano, hydroxyalkyl, —(CH₂)_(p)C(O)OR₆,and —(CH₂)_(p)OC(O)R₆, wherein p is 0, 1, 2, 3, 4, or 5.

In an embodiment, provided is a compound of formula (I-a) or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein R₂ is C₁₋₃ alkoxy (e.g., —OCH₃, —OCH₂CH₂CH₃, —OCH₂CH₃,—OCH(CH₃)₂), C₁₋₄ alkyl (e.g., —CH₃, —CH₂CH₃, —CH₂CH(CH₃)₂), —CH₂OH,—OH, —COOH, —C(O)NH₂, —C(O)NHCH₃, or —CH₂OC(O)CH(NH₂)CH(CH₃)₂, —C(O)NH₂,—C(O)NHCH₃. Preferably R₂ is —CH₃, —C(O)NH₂, —CH₂OH, —OCH₃, or —OH.

In an embodiment, provided is a compound of formula (I-a) or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein R₁ is hydrogen, —CH₃, or —CH₂CH₃. Preferably, R₁ is hydrogen.

In an embodiment, provided is a compound of formula (I-a) or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein R₄ is hydrogen.

In an embodiment, provided is a compound of formula (I-a) or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein R₅ is hydrogen or —CH₃.

In an embodiment, provided is a compound of formula (I-a) or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein each of R₁, R₄, and R₅ is hydrogen.

In an embodiment, provided is a compound of formula (I-a) or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein X is S, S(O), or SO₂.

In an embodiment, provided is a compound of formula (I-a) or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein Y is O, NH, CH₂, or N(CH₃).

In an embodiment, provided is a compound of formula (I-a) or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein X is S and Y is O.

In an embodiment, provided is a compound of formula (I-a) or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein ring B is pyridinyl.

In an embodiment, provided is a compound of formula (I-a) or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein ring B is thiophenyl.

In an embodiment, provided is a compound of formula (I-a) or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein ring B is phenyl.

In an embodiment, provided is a compound of formula (I-a) or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein ring B is pyrazolyl.

In an embodiment, provided is a compound of formula (I-a) or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein ring B is imidazolyl.

In an embodiment, provided is a compound of formula (I-a) or a tautomer,stereoisomer, pharmaceutically acceptable salt, or solvate thereof,wherein ring B is oxazolyl.

In an embodiment, provided is a compound of formula (I-a), or atautomer, stereoisomer, pharmaceutically acceptable salt, or solvatethereof, wherein:

-   -   ring B is pyridinyl;    -   Q is CH or N;    -   each of R₁, R₄ and R₅ is hydrogen;    -   R₂ is selected from the group consisting of alkyl, amide,        hydroxyl, alkoxy, and hydroxylalkyl;    -   X is S; and    -   Y is O.

Exemplary compounds of the application include, but are not limited to,compounds listed in Table 1 below, and any tautomer, stereoisomer,pharmaceutically acceptable salt or solvate thereof. The MMP-12 IC₅₀values were determined according to the assay described in Example 1below. The IC₅₀ values are reported as follows: A=less than 10 nM, B=10nM to 100 nM, C=100 nM to 1000 nM, D=greater than 1000 nM.

TABLE 1 Exemplary Compounds of the Application Compound Analytical Data(LCMS, MMP-12 ID Structure NMR, etc.) IC₅₀ (nM) TC1

¹H-NMR (300 MHz CDCl₃) δ: 7.437 (d, J = 5.1 Hz, 1H), 7.304-7.226 (m,3H), 6.953-6.834 (m, 6H), 5.755 (s, 1H), 5.033 (s, 2H), 3.923 (t, J =6.5 Hz, 2H), 1.758 (tq, J = 7.8 Hz, 2H), 1.036 (t, J = 7.4 Hz, 3H); m/z(ESI+) 453.22 (M−); HPLC tR: 8.033 min. C TC2

¹H-NMR (300 MHz CDCl₃) δ: 7.431 (d, J = 5.4 Hz, 2H), 7.301-7.223 (m,3H), 6.973-6.915 (m, 4H), 6.858-6.826 (m, 2H) 5.751 (s, 1H), 5.026 (s,2H), 4.020 (q, J = 7.2 Hz, 2H), 1.371 (t, J = 7.2 Hz, 3H); m/z (ESI+)439.16 (M−); HPLC tR: 6.066 min. C TC3

¹H-NMR (300 MHz DMSO) δ: 7.435 (d, J = 5.4 Hz, 1H), 7.306-7.248 (m, 3H),6.964-6.851 (m, 6H), 5.752 (s, 1H), 5.032 (s, 2H), 4.586 (qq, J = 6.0Hz, 1H), 1.29 (d, J = 6.0 Hz, 6H); m/z (ESI+) 453.22 (M−); HPLC tR:6.725 min. C TC4

¹H-NMR (300 MHz DMSO) δ: 8.529 (bs, 1H), 7.574 (d, J = 5.1 Hz, 1H),7.366-7.256 (m, 6H), 6.976 (d, J = 8.7 Hz, 2H) 6.860 (d, J = 5.1 Hz, H),5.647 (s, 1H), 5.225-5.188 (m, 1H), 5.188-5.057 (m, 2H), 4.482 A (d, J =5.7 Hz, 2H); m/z (ESI+) 449.43 (M + Na)+; HPLC tR: 3.917 min. TC5

¹H-NMR (300 MHz DMSO) δ: 8.547 (bs, 1H), 7.595 (d, J = 5.1 Hz, 1H),7.474-7.260 (m, 6H), 7.010-6.988 (m, 2H), 6.888 (d, J = 5.1 Hz, 1H),5.556 (s, 1H), 5.198-5.130 (m, 2H), 4.585 (d, J = 5.1 Hz, 2H); m/z(ESI+) 449.16 A (M + Na)+; HPLC tR: 3.436 min. TC6

¹H-NMR (300 MHz DMSO) δ: 10.942 (bs, 1H), 8.545 (s, 1H), 7.88 (d, J =5.4 Hz, 1H), 7.392-7.267 (m, 6H), 6.981 (d, J = 8.7 Hz, 2H) 6.871 (d, J= 5.4 Hz, H), 5.663 (s, J = 1.2 Hz, 1H), 5.118 (t, J = 5.7 A Hz, 1H),5.065 (s, 2H), 4.486 (d, J = 6 Hz, 2H); m/z (ESI+) 449.17 (M + Na)+;HPLC tR: 6.435 min. TC7

¹H-NMR (300 MHz CDCl₃) δ: 7.418 (d, J = 5.4 Hz, 1H), 7.289-7.261 (m,2H), 7.185-7.133 (m, 1H), 6.924-6.839 (m, 5H), 6.731-6.701 (m, 1H),5.743 (s, 1H), 4.988 (s, 2H); m/z (ESI+) 412.00 (M+−); HPLC tR: 6.586min. A TC8

¹H-NMR (300 MHz CDCl₃) δ: 10.935 (s, 1H), 8.532 (s, 1H), 8.403 (d, J =5.4 Hz, 1H) 7.576 (d, J = 5.4 Hz, 1H), 7.286-7.178 (m, 4H), 6.973 (d, J= 8.7 Hz, 2H), 6.861 (d, J = 5.4 Hz, 1H), 5.698 (s, 1H), A 5.298 (s,2H), 2.482-2.443 (m, 3H); m/z (ESI+) 412.24 (M + Na)+; HPLC tR: 6.035min. PC-1

¹H NMR (400 MHz, CD₃OD) δ 8.297 (d, J = 5.2 Hz, 1H), 7.23 (d, J = 7.6Hz, 1H), 7.385 (d, J = 11.2 Hz, 2H), 7.237 (dd, J = 7.6, 9.6 Hz, 4H),7.137 (d, J = 6.8 Hz, 2H), 7.011 (d, J = 9.2 Hz, 1H), 5.66 (s, 2H),4.872 (m, 2H), 2.347 (s, 3H); m/z (ESI+) (M + H)+ = 406.25; HPLC tR =7.213 min. B PC-2

¹H NMR (400 MHz, CD₃OD) δ 8.672 (s, 1H), 8.396 (d, J = 6.4 Hz, 1H),7.563 (d, J = 8.8 Hz, 2H), 7.281-7.148 (m, 7H), 5.809 (s, 2H), 5.145 (s,2H), 2.358 (s, 3H); m/z (ESI+) (M + H)+ = 406.15; HPLC tR = 6.254 min. BPC-3

¹H NMR (400 MHz, CD₃OD) δ 8.366 (dd, J = 0.8, 1.6 Hz, 1H), 7.475 (d, J =9.2 Hz, 1H), 7.447 (d, J = 8.8 Hz, 2H), 7.279-7.218 (m, 4H), 7.143 (s,1H), 7.052 (d, J = 9.2 Hz, 2H), 5.849 (s, 2H), 5.115 (s, 2H), 2.345 (s,3H); m/z (ESI+) (M + H)+ = 406.15; HPLC tR = 7.317 min. B PC-4

¹H NMR (400 MHz, CD₃OD) δ 7.431 (d, J = 8.8 Hz, 3H), 7.247-7.215 (m,4H), 7.137 (d, J = 8.0 Hz, 2H), 7.040 (d, J = 8.8 Hz, 2H), 5.792 (s,2H), 4.824 (s, 2H), 2.343 (s, 3H); m/z (ESI+) (M + H)+ = 406.1; HPLC tR= 6.553 min. B PC-5

¹H NMR (400 MHz, CD₃OD) δ 8.818 (d, J = 5.2 Hz, 1H), 8.654 (s, 1H),7.989 (d, J = 4.8 Hz, 1H), 7.782 (d, J = 8.4 Hz, 2H), 7.260-7.120 (m,6H), 5.789 (s, 1H), 5.155 (s, 2H), 2.331 (s, 3H); m/z (ESI+) (M − H)− =420; HPLC tR = 6.378 min. C PC-6

¹H NMR (400 MHz, CD₃OD) δ 8.785 (d, J = 5.2 Hz, 1H), 8.690 (s, 1H),7.955 (dd, J = 8.8, 5.2 Hz, 3H), 7.248 (s, 2H), 7.213 (d, J = 2.8 Hz,3H), 7.182 (s, 1H), 6.345 (s, 1H), 5.141 (s, 2H), 2.335 (s, 3H); m/z(ESI+) (M − H)− = 436.1; HPLC tR = 6.544 min. C PC-7

¹H NMR (400 MHz, CD₃OD) δ 8.33 (s, 1H), 8.19 (d, J = 5.9 Hz, 1H),7.49-7.41 (m, 4H), 7.37 (d, J = 11.9 Hz, 2H), 7.12 (d, J = 8.7 Hz, 2H),6.76 (s, 1H), 5.57 (s, 1H), 5.14 (s, 2H), 4.61 (s, 2H); m/z (ESI+) (M +H)+ = 422.10; HPLC tR = 5.271 min. B PC-8

¹H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.37 (d, J = 12.2 Hz, 2H),8.28 (s, 1H), 7.52-7.38 (m, 3H), 7.30 (d, J = 17.6 Hz, 3H), 7.16 (d, J =7.1 Hz, 2H), 6.65 (s, 1H), 5.49 (s, 1H), 5.24 (s, 1H), 5.14 (s, 2H),4.50 (s, 2H), 4.11 (s, 1H); m/z (ESI+) (M + H)+ = 422.15; HPLC tR =5.282 min. A PC-9

¹H NMR (400 MHz, CD₃OD) δ 8.33 (s, 1H), 8.18 (s, 1H), 7.46 (d, J = 6.3Hz, 4H), 7.37-7.27 (m, 2H), 7.15 (d, J = 8.7 Hz, 2H), 6.78 (d, J = 5.4Hz, 1H), 5.57 (s, 1H), 5.24 (s, 2H), 4.73 (s, 2H); m/z (ESI+) (M + H)+ =422.15; HPLC tR = 5.383 min. B PC-10

¹H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.36 (d, J = 7.9 Hz, 2H), 8.27(s, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.20-7.09 (m, 3H), 6.84 (d, J = 11.9Hz, 2H), 6.74-6.61 (m, 2H), 5.48 (s, 1H), 5.06 (s, 2H); m/z (ESI+) (M +H)+ = 408.10; HPLC tR = 5.309 min. A PC-11

¹H NMR (400 MHz, CD₃OD) δ 8.68 (s, 1H), 8.41 (s, 1H), 7.66-7.54 (m, 2H),7.46 (d, J = 18.1 Hz, 2H), 7.25 (d, J = 9.0 Hz, 2H), 5.81 (s, 1H), 5.34(dd, J = 29.1, 12.2 Hz, 2H), 5.21 (s, 2H), 3.98 (s, 1H), 3.85 (s, 1H),2.99 (s, 1H), 2.86 (s, 1H), 2.29 (s, 1H), 2.03 (s, 1H), 1.29 (s, 3H),1.03 (t, J = 14.5 Hz, 3H), 0.90 (s, 1H); m/z (ESI+) (M + H)+ = 521.25;HPLC tR = 5.165 min. B PC-12

¹H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.46-8.34 (m, 2H), 8.27 (s,1H), 7.50-7.19 (m, 7H), 7.04 (d, J = 8.9 Hz, 2H), 5.66 (s, 1H), 5.20-5.10 (m, 3H), 4.57 (d, J = 5.4 Hz, 2H); m/z (ESI+) (M + H)+ = 422.00;HPLC tR = 5.591 min. A PC-13

¹H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.46-8.36 (m, 2H), 8.27 (s,1H), 7.38 (d, J = 8.8 Hz, 3H), 7.36-7.22 (m, 4H), 7.04 (d, J = 8.9 Hz,2H), 5.66 (s, 1H), 5.20 (d, J = 5.7 Hz, 1H), 5.09 (s, 2H), 4.49 (d, J =5.8 Hz, 2H); m/z (ESI+) (M + H)+ = 422.05; HPLC tR = 5.522 min. A PC-14

¹H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.45-8.36 (m, 2H), 8.26 (s,1H), 7.42-7.27 (m, 7H), 7.03 (d, J = 8.8 Hz, 2H), 5.66 (s, 1H), 5.18 (t,J = 5.7 Hz, 1H), 5.08 (s, 2H), 4.48 (d, J = 5.7 Hz, 2H); m/z (ESI+) (M +H)+ = 422.05; HPLC tR = 5.483 min. B PC-15

¹H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.47-8.35 (m, 2H), 8.27 (s,1H), 7.44-7.28 (m, 3H), 7.15 (t, J = 7.7 Hz, 1H), 7.06-6.96 (m, 2H),6.82 (d, J = 8.0 Hz, 2H), 6.73-6.65 (m, 1H), 5.67 (s, 1H), 5.02 (s, 2H);m/z (ESI+) (M + H)+ = 408.10; HPLC tR = 5.607 min. A PC-16

¹H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.41 (dd, J = 22.7, 9.8 Hz,1H), 8.27 (d, J = 5.4 Hz, 3H), 7.46 (d, J = 8.7 Hz, 2H), 7.30 (s, 2H),7.23 (d, J = 4.8 Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 6.65 (d, J = 5.3 Hz,1H), 5.74 (s, 1H), 5.49 (s, 2H), 2.46 (s, 3H); m/z (ESI+) (M − H)− =407.15; HPLC tR = 3.792 min. A PC-17

¹H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.82-8.30 (m, 5H), 8.21 (s,1H), 7.51 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H), 6.80 (d, J =5.7 Hz, 1H), 5.69 (s, 1H), 5.56 (s, 1H), 5.28 (s, 1H), 2.44 (s, 3H); m/z(ESI+) (M − H)− = 405.25; HPLC tR = 4.332 min. C PC-18

¹H NMR (400 MHz, CD₃OD) δ 8.39 (d, J = 5.4 Hz, 3H), 8.25 (s, 1H), 7.42(dd, J = 17.8, 10.4 Hz, 5H), 7.31 (d, J = 5.4 Hz, 1H), 7.05 (d, J = 8.6Hz, 2H), 5.79 (s, 1H), 5.49 (s, 1H), 5.17 (s, 2H), 2.54 (s, 4H); m/z(ESI+) (M + H)+ = 407.15; HPLC tR = 5.028 min. A PC-19

¹H NMR (400 MHz, CD₃OD) δ 8.38 (dd, J = 17.8, 12.6 Hz, 3H), 8.24 (s,1H), 7.76 (s, 1H), 7.42 (t, J = 7.4 Hz, 3H), 7.05 (d, J = 8.8 Hz, 2H),5.79 (s, 1H), 5.13 (s, 2H), 2.37 (d, J = 6.4 Hz, 4H); m/z (ESI+) (M +H)+ = 407.15; HPLC tR = 4.600 min. C PC-20

¹H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.71 (d, J = 4.5 Hz, 1H),8.36 (dd, J = 39.9, 8.9 Hz, 3H), 8.10 (s, 1H), 7.67 (s, 1H), 7.49 (d, J= 8.5 Hz, 2H), 7.20 (d, J = 8.5 Hz, 3H), 6.72 (d, J = 5.6 Hz, 1H), 5.52(s, 1H), 5.34 (s, 2H); m/z (ESI+) (M + H)+ = 437.1; HPLC tR = 4.332 min.D PC-21

¹H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.97 (d, J = 56.5 Hz, 2H),8.60-8.26 (m, 4H), 7.51 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H),6.81 (d, J = 5.5 Hz, 1H), 5.57 (s, 1H), 5.31 (s, 2H); m/z (ESI+) (M +H)+ = 437.1; HPLC tR = 4.527 min. D PC-22

¹H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.64-8.11 (m, 3H), 7.47- 6.98(m, 7H), 6.63 (s, 1H), 5.07 (s, 2H), 2.28 (d, J = 4.9 Hz, 3H), 2.26-2.18(m, 2H), 0.92 (s, 3H); m/z (ESI+) (M + H)+ = 434.15; HPLC tR = 5.750min. A PC-23

¹H NMR (400 MHz, DMSO-d6) δ 10.82 (d, J = 0.8 Hz, 1H), 8.42 (dd, J =29.8, 4.6 Hz, 2H), 8.21 (s, 1H), 8.00 (d, J = 1.7 Hz, 1H), 7.88 (d, J =3.1 Hz, 1H), 7.67 (d, J = 2.7 Hz, 1H), 7.51 (d, J = 2.8 Hz, 1H),7.17-6.91 (m, 4H), 6.62 (d, J = 1.5 Hz, 1H), 5.33 (d, J = 3.2 Hz, 1H),5.17 (d, J = 1.9 Hz, 2H); m/z (ESI+) (M + H)+ = D 420.15; HPLC tR =6.453 min. PC-24

¹H NMR (400 MHz, CD₃OD) δ 9.100 (s, 1H), 8.858 (s, 1H), 8.535 (s, 1H),8.429 (d, J = 6.4 Hz, 1H), 8.256 (s, 1H), 7.498 (d, J = 11.6 Hz, 3H),7.133 (d, J = 11.6 Hz, 2H), 5.835 (s, 1H), 5.237 (s, 3H); m/z (ESI+)(M + H)+ = 437.1; HPLC tR = 4.778 min. D PC-25

¹H NMR (400 MHz, CD₃OD) δ 8.45 (s, 1H), 8.36 (d, J = 5.8 Hz, 1H), 7.46(s, 1H), 7.34 (d, J = 11.5 Hz, 3H), 7.06 (q, J = 9.2 Hz, 4H), 6.71 (d, J= 5.8 Hz, 1H), 5.40 (s, 1H), 5.11 (s, 2H), 4.62 (s, 2H); m/z (ESI+) (M +H)+ = 406.25; HPLC tR = 5.024 min. B PC-26

¹H NMR (400 MHz, CD₃OD) δ 8.45 (s, 1H), 8.36 (d, J = 5.8 Hz, 1H),7.30-7.19 (m, 3H), 7.16- 6.99 (m, 5H), 6.70 (d, J = 5.8 Hz, 1H), 5.40(s, 1H), 5.06 (s, 2H), 2.35 (s, 3H); m/z (ESI+) (M + H)+ = 390.2; HPLCtR = 5.780 min. B PC-27

¹H NMR (400 MHz, CD₃OD) δ 8.46 (s, 1H), 8.38 (dd, J = 9.4, 5.5 Hz, 2H),7.42-7.28 (m, 2H), 7.13-7.03 (m, 4H), 6.72 (d, J = 5.8 Hz, 1H), 5.49 (s,1H), 5.40 (s, 1H), 5.16 (s, 2H), 2.54 (s, 3H); m/z (ESI+) (M + H)+ =391.3; HPLC tR = 3.846 min. B PC-28

¹H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.37 (d, J = 5.1 Hz, 2H),8.28 (d, J = 5.4 Hz, 1H), 7.98 (d, J = 12.2 Hz, 1H), 7.84 (d, J = 7.8Hz, 2H), 7.61 (d, J = 7.5 Hz, 1H), 7.51-7.35 (m, 4H), 7.17 (d, J = 8.6Hz, 2H), 6.66 (d, J = 5.3 Hz, 1H), 5.49 (s, 1H), 5.20 (s, 2H); m/z(ESI+) (M + H)+ = 435.15; HPLC tR = 4.567 min. A PC-29

¹H NMR (400 MHz, CDCl₃) δ 8.23 (s, 1H), 8.08 (d, J = 5.5 Hz, 1H), 7.79(s, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.39-7.34(m, 4H), 6.96 (d, J = 8.5 Hz, 2H), 6.63 (d, J = 5.5 Hz, 1H), 5.40 (s,1H), 5.05 (s, 3H), 2.87 (s, 3H); m/z (ESI+) (M + H)+ = 449.2; HPLC tR =5.091 min. B PC-30

¹H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.36 (d, J = 4.7 Hz, 2H),8.28 (d, J = 5.3 Hz, 1H), 8.16 (d, J = 5.3 Hz, 1H), 7.46 (d, J = 8.4 Hz,2H), 7.15 (d, J = 8.2 Hz, 2H), 7.03 (d, J = 5.1 Hz, 1H), 6.86 (s, 1H),6.65 (d, J = 5.5 Hz, 1H), 5.49 (s, 1H), 5.19 (s, 2H), 3.84 (s, 3H); m/z(ESI+) (M + H)+ = 423.25; HPLC tR = 5.057 min. B PC-31

¹H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 3.4 Hz, 2H), 8.28 (d, J = 5.4Hz, 1H), 8.14 (d, J = 5.2 Hz, 1H), 7.46 (d, J = 8.2 Hz, 2H), 7.15 (d, J= 8.3 Hz, 2H), 7.00 (d, J = 5.3 Hz, 1H), 6.82 (s, 1H), 6.66 (d, J = 5.4Hz, 1H), 5.49 (s, 1H), 5.18 (s, 2H), 4.29 (q, J = 7.0 Hz, 2H), 1.29 (dd,J = 7.4, 6.7 Hz, 3H); m/z (ESI+) (M + H)+ = 437.2; HPLC tR = 5.204 min.B PC-32

¹H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 4.1 Hz, 2H), 8.27 (d, J = 5.4Hz, 1H), 8.13 (d, J = 5.3 Hz, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.15 (d, J= 8.6 Hz, 2H), 6.98 (d, J = 5.1 Hz, 1H), 6.77 (s, 1H), 6.66 (d, J = 5.4Hz, 1H), 5.49 (s, 1H), 5.23 (dt, J = 12.3, 6.1 Hz, 1H), 5.17 (s, 2H),1.27 (d, J = 6.2 Hz, 6H); m/z (ESI+) (M + H)+ = 451.25; HPLC tR = 5.365min. B PC-33

¹H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.36 (s, 2H), 8.27 (d, J =5.4 Hz, 1H), 8.13 (d, J = 5.2 Hz, 1H), 7.46 (d, J = 8.8 Hz, 2H), 7.15(d, J = 8.8 Hz, 2H), 7.01 (d, J = 5.1 Hz, 1H), 6.85 (s, 1H), 6.65 (d, J= 5.4 Hz, 1H), 5.49 (s, 1H), 5.18 (s, 2H), 4.02 (d, J = 6.7 Hz, 2H),2.00 (dt, J = 13.4, 6.7 Hz, 1H), 0.94 (d, J = 6.7 Hz, 6H); m/z (ESI+)(M + H)+ = 465.25; HPLC tR = 5.690 min. C PC-34

¹H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.00 (d, J = 1.9 Hz, 1H),8.81 (d, J = 1.8 Hz, 1H), 8.36 (s, 2H), 8.31-8.27 (m, 2H), 8.20 (s, 1H),7.64 (s, 1H), 7.47 (d, J = 8.7 Hz, 2H), 7.20 (d, J = 8.8 Hz, 2H), 6.66(d, J = 5.3 Hz, 1H), 5.49 (s, 1H), 5.26 (s, 2H); m/z (ESI+) (M + H)+ =436.15; HPLC tR = 4.312 min. B PC-35

¹H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.37 (t, J = 22.6 Hz, 3H),7.47 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 6.7 Hz, 1H), 7.15 (d, J = 8.6 Hz,2H), 6.72 (d, J = 5.3 Hz, 1H), 6.36 (s, 1H), 6.19 (d, J = 6.7 Hz, 1H),5.52 (s, 1H), 5.04 (s, 2H); m/z (ESI+) (M + H)+ = 409; HPLC tR = 4.665min. C PC-36

¹H NMR (400 MHz, CD3OD) δ 8.94 (d, J = 2.1 Hz, 1H), 8.79 (d, J = 2.1 Hz,1H), 8.35 (s, 2H), 8.20 (d, J = 5.5 Hz, 1H), 7.51 (s, 2H), 7.21 (s, 2H),6.79 (d, J = 5.5 Hz, 1H), 5.58 (s, 1H), 5.28 (s, 2H), 2.95 (s, 3H); m/z(ESI+) (M + H)+ = 450.1; HPLC tR = 4.221 min. C PC-37

¹H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 4.4 Hz, 2H), 8.28 (d, J = 5.3Hz, 1H), 7.97 (s, 1H), 7.89 (d, J = 7.8 Hz, 2H), 7.52 (d, J = 7.8 Hz,2H), 7.45 (d, J = 8.2 Hz, 2H), 7.36 (s, 1H), 7.16 (d, J = 8.3 Hz, 2H),6.65 (d, J = 5.6 Hz, 1H), 5.49 (s, 1H), 5.21 (s, 2H); m/z (ESI+) (M +H)+ = 435.1; HPLC tR = 5.069 min. C PC-38

¹H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.64 (d, J = 5.3 Hz, 1H), 8.31(s, 1H), 8.23 (d, J = 5.4 Hz, 1H), 8.16 (s, 1H), 7.67 (s, 1H), 7.58 (d,J = 4.7 Hz, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.11 (d, J = 8.5 Hz, 3H),6.63 (d, J = 5.1 Hz, 1H), 5.40 (s, 3H), 5.36 (s, 1H); m/z (ESI+) (M +H)+ = 436.10; HPLC tR = 4.842 min. D PC-39

¹H NMR (400 MHz, CD3OD) δ 8.54 (s, 1H), 8.50 (s, 1H), 8.35-8.31 (m, 1H),8.20-8.15 (m, 1H), 7.94 (s, 1H), 7.52- 7.45 (m, 2H), 7.20-7.13 (m, 2H),6.77 (d, J = 5.5 Hz, 1H), 5.58-5.55 (m, 1H), 5.25-5.20 (m, 1H),4.70-4.66 (m, 2H), 4.53 (s, 1H), 3.34-3.27 (m, 3H). m/z (ESI+) (M + H)+= 423.20; HPLC tR = 1.472 min. C PC-40

¹H NMR (400 MHz, CD3OD) δ 8.45 (d, J = 5.1 Hz, 1H), 8.33 (s, 1H), 8.18(d, J = 5.5 Hz, 1H), 7.66 (s, 1H), 7.53-7.47 (m, 2H), 7.39 (d, J = 4.5Hz, 1H), 7.15 (d, J = 8.9 Hz, 2H), 6.77 (d, J = 5.5 Hz, 1H), 5.56 (s,1H), 5.25 (s, 2H), 4.70 (s, 2H). m/z (ESI+) (M + H)+ = 423.10; HPLC tR =4.305 min. A PC-41

¹H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 5.1 Hz, 1H), 8.37 (s, 1H), 8.26(d, J = 5.4 Hz, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.22 (s, 1H), 7.16 (d, J= 5.0 Hz, 1H), 7.02 (d, J = 8.4 Hz, 2H), 6.69 (d, J = 5.4 Hz, 1H), 6.48(s, 1H), 5.45 (s, 1H), 5.08 (s, 2H), 3.11 (s, 3H), 2.58 (s, 3H). m/z(ESI+) (M + H)+ = 421.15; HPLC tR = 4.384 min. C PC-42

1H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 5.2 Hz, 1H), 8.42 (s, 1H), 8.25(d, J = 5.6 Hz, 1H), 7.47 (m, 1H), 7.23 (s, 1H), 7.16 (m, 1H), 6.98 (m,1H), 6.69 (m, 1H), 6.52 (m, 1H), 6.11 (m, 1 H), 5.54 (s, 1H), 5.08 (s,2H), 2.60 (s, 3H), 2.28 (s, 3H). m/z (ESI+) (M + H)+ = 421.10; HPLC tR =4.265 min. B PC-43

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 8.23 (d, J = 5.5 Hz, 1H),7.61-7.53 (m, 6H), 7.14 (t, J = 7.9 Hz, 1H), 6.87 (d, J = 5.5 Hz, 1H),6.79 (dd, J = 17.0, 9.6 Hz, 3H), 5.61 (s, 1H), 5.12 (s, 2H), 2.30 (s,3H). m/z (ESI+) (M + H)+ = 406.10; HPLC tR = 5.862 min. D PC-44

¹H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 5.1 Hz, 1H), 8.32 (s, 1H), 8.23(s, 1H), 7.47-7.40 (m, 2H), 7.30 (s, 1H), 7.23 (dd, J = 5.2, 1.6 Hz,1H), 7.18-7.09 (m, 2H), 6.53 (s, 1H), 5.44 (s, 1H), 5.19 (d, J = 6.9 Hz,2H), 2.46 (d, J = 2.2 Hz, 2H), 2.25 (d, J = 2.2 Hz, 3H). m/z (ESI+) (M +H)+ = 407.15; HPLC tR = 3.843 min. B PC-45

¹H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 5.1 Hz, 1H), 8.32 (s, 1H), 8.23(s, 1H), 7.47-7.42 (m, 2H), 7.30 (s, 1H), 7.23 (d, J = 4.2 Hz, 1H),7.18- 7.11 (m, 2H), 6.53 (s, 1H), 5.44 (s, 1H), 5.19 (s, 2H), 2.46 (s,3H), 2.25 (s, 3H). m/z (ESI+) (M + H)+ = 421.10; HPLC tR = 3.941 min. BPC-46

¹H NMR (400 MHz, CDCl₃) δ 8.57 (s, 1H), 8.52 (d, J = 4.8 Hz, 1H), 8.26(d, J = 5.6 Hz, 1H), 7.45 (m, 2H), 7.22 (s, 1H), 7.16 (m, 1H), 7.01 (d,J = 8.8 Hz, 2H), 6.66 (d, J = 5.6 Hz, 1H), 5.08 (s, 2H), 3.14 (s, 3H),2.75 (s, 3H), 2.59 (s, 3H), 1.93 (s, 3H). m/z (ESI+) (M + H)+ = 449.15;HPLC tR = 4.478 min. D PC-47

¹H NMR (400 MHz, CD₃OD) δ 8.71 (m, 2H), 8.46-8.37 (m, 1H), 8.32 (s, 1H),8.25 (s, 1H), 7.47 (d, J = 8.8 Hz, 3H), 7.10 (d, J = 8.8 Hz, 2H), 5.80(s, 1H), 5.29 (s, 3H). m/z (ESI+) (M + H)+ = 423.20; HPLC tR = 4.554min. D PC-48

¹H NMR (400 MHz, CD₃OD) δ 8.42 (d, J = 5.2 Hz, 1H), 8.33 (s, 1H), 8.19(d, J = 5.6 Hz, 1H), 7.38 (m, 1 H), 7.36 (m, 3H), 7.07 (d, J = 9.2 Hz,1H), 6.79 (d, J = 5.6 Hz, 1H), 5.57 (s, 1H), 5.23 (s, 2H), 2.56 (s, 3H),2.32 (s, 3H); m/z (ESI+) (M + H)+ = 421.15; HPLC tR = 5.222 min. A PC-49

¹H NMR (400 MHz, CD₃OD) δ 8.42 (d, J = 5.2 Hz, 1H), 8.37 (s, 1H), 8.24(d, J = 5.6 Hz, 1H), 7.64 (m, 1 H), 7.38-7.25 (m, 4H), 6.83 (d, J = 5.6Hz, 1H), 5.54 (s, 1H), 5.30 (s, 2H), 2.56 (s, 3H); m/z (ESI+) (M + H)+ =441.10; HPLC tR = 4.186 min. B PC-50

¹H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 8.46-8.41 (m, 2H), 8.39 (s, 1H),8.29 (d, J = 5.3 Hz, 1H), 7.55 (t, J = 8.6 Hz, 1H), 7.30 (s, 1H), 7.26-7.15 (m, 2H), 7.06-7.00 (m, 1H), 6.64 (d, J = 5.3 Hz, 1H), 5.53 (s, 1H),5.21 (s, 2H), 2.47 (s, 3H); m/z (ESI+) (M + H)+ = 425.10; HPLC tR =4.416 min. A PC-51

¹H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 8.45 (d, J = 5.6 Hz, 2H), 8.40(s, 1H), 8.29 (d, J = 5.3 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.41 (d, J= 2.7 Hz, 1H), 7.30 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 7.14 (dd, J =8.7, 2.7 Hz, 1H), 6.58 (d, J = 5.3 Hz, 1H), 5.53 (d, J = 1.1 Hz, 1H),5.22 (s, 2H), 2.50- 2.48 (m, 3H); m/z (ESI+) (M + H)+ = 441.20; HPLC tR= 7.101 min. A PC-52

¹H NMR (400 MHz, DMSO) δ 8.45 (d, J = 5.0 Hz, 1H), 8.39 (s, 2H), 8.31(d, J = 5.3 Hz, 1H), 7.45 (d, J = 10.1 Hz, 1H), 7.32 (t, J = 8.6 Hz,3H), 7.23 (d, J = 4.2 Hz, 1H), 6.78 (d, J = 5.2 Hz, 1H), 5.50 (s, 1H),5.26 (s, 2H), 2.47 (s, 4H); m/z (ESI+) (M + H)+ = 425.20; HPLC tR =6.742 min. B PC-53

¹H NMR (400 MHz, CD₃OD) δ 8.66-8.64 (m, 1H), 8.41-8.39 (m, 1H),8.24-8.23 (m, 1H), 8.02- 8.01 (m, 1H), 7.94-7.91 (m, 1H), 7.43 (m, 3H),7.11- 7.08 (m, 2H), 5.78-5.78 (m, 1H), 5.43-5.42 (m, 2H), 4.82-4.82 (m,2H); m/z (ESI+) (M + H)+ = 423.05; HPLC tR = 4.514 min. B PC-54

¹H NMR (400 MHz, CD₃OD) δ 8.69 (d, J = 6.2 Hz, 1H), 8.49 (s, 1H), 8.32(d, J = 5.8 Hz, 1H), 8.01 (s, 1H), 7.94 (d, J = 5.4 Hz, 1H), 7.55 (s,2H), 7.27 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 5.6 Hz, 1H), 5.48 (s, 3H),3.08 (s, 3H), 2.90 (s, 3H), 2.81 (s, 3H); m/z (ESI+) (M + H)+ = 435.10;HPLC tR = 4.199 min. D PC-55

¹H NMR (400 MHz, CDCl₃) δ 8.52 (d, J = 5.2 Hz, 1H), 8.31 (s, 1H), 8.24(d, J = 5.4 Hz, 1H), 7.37 (dd, J = 11.8, 8.6 Hz, 4H), 7.24 (s, 1H), 7.18(d, J = 4.9 Hz, 1H), 6.99 (d, J = 8.7 Hz, 2H), 6.76 (d, J = 8.6 Hz, 2H),6.66 (d, J = 5.4 Hz, 1H), 6.19 (s, 1H), 5.40 (s, 1H), 5.09 (s, 2H), C4.68 (s, 2H), 3.70 (s, 3H), 2.60 (s, 3H); m/z (ESI+) (M + H)+ = 527.20;HPLC tR = 5.118 min. PC-56

¹H NMR (400 MHz, CD₃OD) δ: 8.309 (d, J = 5.2 Hz, 1H), 8.262 (s, 1H),8.149 (d, J = 5.2 Hz, 1H), 7.281-7.225 (m, 4H), 6.756 (d, J = 5.6 Hz,1H), 6.669 (d, J = 8.8 Hz, 2H), 5.517 (s, 1H), 4.393 (s, 2H), 2.487 (s,3H); m/z (ESI+) (M + H)+ = 406.30, (M − H)− = 404.20; HPLC tR = 4.831min. B PC-57

¹H-NMR (400 MHz DMSO) δ: 10.997 (s, 1H), 8.369 (s, 2H), 8.281 (d, J =5.2 Hz, 2H), 7.399-7.326 (m, 4H), 7.082 (s, 1H), 7.017 (d, J = 5.2 Hz,1H), 6.665 (d, J = 5.2 Hz, 1H), 5.486 (s, 1H), 2.917-2.846 (m, 4H),2.378 (s, 3H); m/z (ESI+) (M + H)+ = 405.25; HPLC tR = 3.645 min. BPC-58

¹H NMR (400 MHz, CD₃OD) δ: 8.577-8.545 (m, 2H), 8.319 (s, 1H),7.741-7.686 (m, 2H), 7.393 (s, 2H), 7.100 (s, 1H), 6.873 (s, 2H), 5.703(s, 1H), 4.923-4.868 (m, 2H), 3.232 (s, 3H), 2.752 (s, 3H); m/z (ESI+)(M + H)+ = 420.25; HPLC tR = 3.637 min. B PC-59

¹H NMR (400 MHz, CD₃OD) δ: 8.607 (d, J = 5.2 Hz, 1H), 8.376 (d, J = 5.2Hz, 1H), 8.247 (s, 1H), 8.173 (s, 1H), 7.837 (s, 1H), 7.604-7.596 (m,1H), 7.430 (d, J = 9.2 Hz, 2H), 7.398 (d, J = 5.2 Hz, 1H), 7.058 (d, J =8.8 Hz, 2H), 5.772 (s, 1H), 5.447 (s, 1H), 5.237 (s, 2H); m/z (ESI+)(M + H)+ = 436.25, (M − H) 434.20; HPLC tR = 4.762 min. C PC-60

¹H-NMR (400 MHz DMSO) δ: 10.980 (s, 1H), 8.625 (d, J = 4.8 Hz, 1H),8.345 (s, 1H), 8.269 (d, J = 5.2 Hz, 1H), 8.107 (s, 1H), 8.078 (s, 1H),7.646 (s, 1H), 7.624 (d, J = 5.2 Hz, 1H), 7.466 (d, J = 8.8 Hz, 2H),7.176 (d, J = 8.8 Hz, 2H), 6.654 (d, J = 5.2 Hz, 1H), 5.472 (s, 1H),5.326 (s, 1H); m/z (ESI+) (M + H)+ = 436.25, (M − H)− = 434.15; HPLC tR= 4.966 min. B PC-61

¹H NMR (400 MHz, CD₃OD) δ: 8.581 (d, J = 6.4 Hz, 1H), 8.310 (d, J = 5.6Hz, 1H), 8.238 (s, 1H), 7.730 (s, 1H), 7.715 (s, 1H), 7.393 (d, J = 5.6Hz, 1H), 6.927 (s, 1H), 5.094 (d, J = 17.2 Hz, 1H), 4.784 (d, J = 17.2Hz, 1H), 2.77 (s, 3H); m/z (ESI+) (M + H)+ = 408.25, (M − H)− = 406.20;HPLC tR = 2.054 min. C PC-62

¹H NMR (400 MHz, CDCl₃) δ: 8.475 (s, 1H), 8.417 (d, J = 5.6 Hz, 1H),8.352 (d, J = 4.8 Hz, 1H), 7.165 (d, J = 8.4 Hz, 2H), 6.977 (d, J = 8.4Hz, 3H), 6.886 (d, J = 5.2 Hz, 1H), 6.595 (d, J = 5.6 Hz, 1H), 6.087 (s,1H), 5.346 (s, 1H), 2.916-2.859 (m, 4H), 2.512 (s, 3H); m/z (ESI+) (M +H)+ = 389.25; HPLC tR = 3.522 min. C PC-63

¹H NMR (400 MHz, CDCl₃) δ: 9.146 (bs, 1H), 8.674 (s, 1H), 8.515 (d, J =5.2 Hz, 1H), 8.227 (d, J = 5.2 Hz, 1H), 7.421 (d, J = 8.8 Hz, 2H), 7.219(s, 1H), 7.162 (d, J = 4.4 Hz, 1H), 7.017 (d, J = 8.8 Hz, 2H), 6.696 (d,J = 5.2 Hz, 1H), 6.662 (s, 1H), 5.074 (s, 1H), 2.584 (s, 3H), 2.480-2.426 (m, 1H), 2.343-2.289 (m, 1H), 1.057 (t, J = 7.2 Hz, 3H); m/z(ESI+) (M + H)+ = 435, (M − H)− = 430; HPLC tR = 3.674 min. A PC-64

¹H NMR (400 MHz, CDCl₃) δ: 8.753 (bs, 1H), 8.502 (d, J = 5.2 Hz, 1H),8.402 (d, J = 5.6 Hz, 1H), 8.327 (s, 1H), 7.605 (d, J = 5.2 Hz, 2H),7.295 (d, J = 8.8 Hz, 2H), 7.207 (s, 1H), 7.148 (d, J = 4.8 Hz, 1H),6.930 (d, J = 8.8 Hz, 2H), 5.036 (s, 2H), 2.583 (s, 3H), 2.296-2.163 (m,2H), 1.011 (t, J = 7.2 Hz, 3H); m/z (ESI+) (M + H)+ = 435.30, (M − H)− =433.30; HPLC tR = 3.924 min. A OC-1

¹H NMR (400 MHz, CD₃OD) δ 7.321 (d, J = 9.2 Hz, 3H), 7.260-7.181 (m,6H), 7.131 (s, 1H), 6.971 (d, J = 8.8 Hz, 2H), 5.738 (s, 2H), 5.030 (s,2H), 2.338 (s, 3H); m/z (ESI+) (M + H)+ = 405.1; HPLC tR = 7.747 min. BOC-2

¹H NMR (400 MHz, CD₃OD) δ 8.007 (d, J = 7.2 Hz, 1H), 7.777-7.749 (m,1H), 7.656-7.581 (m, 2H), 7.531 (dd, J = 7.6, 9.2 Hz, 2H), 7.479 (d, J =7.2 Hz, 1H), 7.235 (m, 2H), 7.198 (s, 1H), 7.151-7.079 (m, 3H), 5.648(s, 1 H), 5.078 (s, 2 H), 2.329 (s, 3H); m/z (ESI+) (M + H)+ = 421.1;HPLC tR = 6.849 min. C OC-3

¹H NMR (400 MHz, CD₃OD) δ 8.886 (s, 1H), 8.189 (d, J = 4 Hz, 1H), 7.424(d, J = 8.8 Hz, 2H), 7.268 (d, J = 10.0 Hz, 3H), 7.154-7.103 (m, 3H),6.769 (d, J = 5.6 Hz, 1H), 5.096 (s, 2H), 2.355 (s, 3H); m/z (ESI+) (M +H)+ = 422.2; HPLC tR = 5.706 min. B OC-4

¹H NMR (400 MHz, CD₃OD) δ 8.378 (d, J = 6.8 Hz, 1H), 8.328 (s, 1H),8.097 (d, J = 6.8 Hz, 1H), 7.995 (d, J = 9.2 Hz, 2H), 7.251-7.134 (m,6H), 6.370 (s, 1H), 5.148 (s, 2H), 2.339 (s, 3H); m/z (ESI+) (M − H)− =452.25; HPLC tR = 6.255 min. D OC-5

¹H NMR (400 MHz, CDCl₃) δ 7.53 (s, 1H), 7.24 (dd, J = 13.2, 4.1 Hz, 1H),7.18 (d, J = 7.2 Hz, 2H), 7.12 (s, 1H), 7.08-7.04 (m, 2H), 6.87-6.77 (m,2H), 6.50 (s, 1H), 5.49 (d, J = 0.5 Hz, 1H), 4.93 (s, 2H), 3.83 (s, 3H),2.33 (s, 3H); m/z (ESI+) (M − H)− = 407.15; HPLC tR = 7.094 min. B OC-6

¹H NMR (400 MHz, CD₃OD) δ 7.73 (s, 1H), 7.24-7.19 (m, 4H), 7.16 (d, J =7.9 Hz, 1H), 7.10 (d, J = 7.7 Hz, 1H), 6.89- 6.85 (m, 2H), 5.67 (s, 1H),4.98 (s, 2H), 3.67 (s, 3H), 2.32 (s, 3H); m/z (ESI+) (M + H)+ = 409.1;HPLC tR = 8.891 min. B OC-7

¹H NMR (400 MHz, CD₃OD) δ 8.35 (d, J = 5.3 Hz, 1H), 8.23 (s, 1H), 7.39(d, J = 8.9 Hz, 2H), 7.34 (s, 1H), 7.27 (d, J = 5.1 Hz, 1H), 6.94 (d, J= 8.9 Hz, 2H), 5.11 (s, 2H), 2.51 (s, 3H); m/z (ESI+) (M + H)+ = 397.25;HPLC tR = 4.881 min. A OC-8

¹H-NMR (300 MHz CDCl₃) δ: 7.683 (s, 1H), 7.509 (d, J = 8.7 Hz, 2H),7.288-7.193 (m, 6H), 5.076 (s, 1H), 5.018 (s, 2H), 1.563 (s, 3H); m/z(ESI+) 412.23 (M + Na)+; HPLC tR: 5.234 min. D OC-9

¹H-NMR (300 MHz CDCl₃) δ: 7.684 (s, 1H), 7.534 (d, J = 8.4 Hz, 2H),7.438-7.348 (m, 4H), 6.997 n (d, J = 8.4 Hz, 2H), 5.085 (s, 2H), 4.800(bs, 1H), 4.726-4.711 (m, 2H); m/z (ESI+) 418.19 (M + Na)+; HPLC tR:5.485 min. D OC-10

¹H-NMR (300 MHz CDCl₃) δ: 7.683 (s, 1H), 7.509 (d, J = 8.7 Hz, 2H),7.288-7.193 (m, 6H), 5.076 (s, 1H), 5.018 (s, 2H), 1.563 (s, 3H); m/z(ESI+) 412.23 (M + Na)+; HPLC tR: 5.234 min. B OC-11

¹H NMR (400 MHz, CD₃OD) δ 8.38 (d, J = 5.1 Hz, 1H), 7.95 (s, 1H), 7.54(d, J = 8.9 Hz, 2H), 7.38 (s, 1H), 7.30 (d, J = 4.9 Hz, 1H), 7.06 (d, J= 8.8 Hz, 2H), 5.17 (s, 2H), 5.14 (s, 1H), 2.53 (s, 3H); m/z (ESI+) (M +H)+ = 397.10; HPLC tR = 4.623 min. D OC-12

¹H NMR (400 MHz, CD₃OD) δ: 8.337 (d, J = 5.2 Hz, 1H), 7.491 (s, 1H),7.402 (s, 1H), 7.287 (s, 1H), 7.224 (d, J = 4.8 Hz, 1H), 7.136 (d, J =8.8 Hz, 2H), 6.854 (d, J = 9.2 Hz, 2H), 5.601 (s, 1H), 5.401 (s, 1H),5.043 (s, 2H), 3.867 (s, 3H), 2.501 (s, 3H); m/z (ESI+) (M + H)+ =410.20, (M − H)− = 408.20; HPLC tR = 4.468 min. A OC-13

¹H-NMR (400 MHz DMSO) δ: 11.013 (s, 1H), 8.390 (d, J = 5.2 Hz, 1H),8.197 (s, 1H), 7.729 (s, 1H), 7.233 (s, 1H), 7.163 (d, J = 8.8 Hz, 3H),6.892 (d, J = 8.8 Hz, 2H), 5.511 (s, 1H), 5.064 (s, 2H), 3.521 (s, 3H),2.427 (s, 3H); m/z (ESI+) (M + H)+ = 410.25, (M − H)− = 408.15; HPLC tR= 5.139 min. A OC-14

¹H-NMR (400 MHz DMSO) δ: 10.699 (s, 1H), 8.395 (d, J = 5.2 Hz, 1H),8.127 (s, 1H), 7.851 (s, 1H), 7.238 (s, 1H), 7.187 (d, J = 8.8 Hz, 2H),6.950 (d, J = 8.8 Hz, 2H), 5.160 (s, 1H), 5.077 (s, 2H), 3.423 (s, 3H),2.428 (s, 3H); m/z (ESI+) (M + H)+ = 410.20; HPLC tR = 4.608 min. B

Compounds of the application can be prepared by any number of processesas described generally below and more specifically illustrated by theexemplary examples. which follow herein. For example, compounds of theapplication can by prepared according to any one of General Schemes 1 to9. In particular, compounds in which X is S, Y is O and Z is CH₂ can beprepared as shown in General Schemes 1-4 and 9; compounds in which eachof X and Y is O and Z is CH₂ can be prepared as shown in General Scheme5; compounds in which X is S, Y is CH₂ and Z is O can be prepared asshown in General Scheme 6; compounds in which X is S, Y is NH and Z isCH₂ can be prepared as shown in General Scheme 7; and compounds in whichX is S and each of Y and Z is CH₂ can be prepared as shown in GeneralScheme 8.

A solution of Int-A an Int-B in an organic solvent is prepare and sodiumhydroxide is added to the solution to form a reaction mixture. Thereaction mixture is stirred overnight then mixed with water and anorganic solvent and extracted. The organic layer is dried and evaporatedunder high vacuum and the residue is purified by column chromatographyto Int-C. Int-C is then mixed with Int-D and potassium carbonate in anorganic solvent and the reaction is monitored by thin layerchromatography (TLC). Once formation of Int-E is confirmed by TLC, thereaction mixture is extracted, and the organic layer dried andevaporated under high vacuum. The residue is purified by columnchromatography to obtain Int-E. Int-E is then reacted with (NH₄)₂CO₃ andpotassium cyanide (KCN) in aqueous alcohol overnight. The reactionmixture is evaporated to remove the solvent and then extracted. Theorganic layer is dried and evaporated, and the residue purified bycolumn chromatography to obtain compounds according to embodiments ofthe application.

A mixture of Int-B in DMSO is stirred overnight with heating undernitrogen atmosphere. Then the mixture is diluted with water andextracted. The organic layer is washed with brine, dried, filtered andconcentrated to give Int-F. A mixture of Int-F, Int-D and potassiumcarbonate is stirred with heating under nitrogen atmosphere. The mixtureis diluted with water and extracted. The organic layer is washed withbrine, dried, filtered, concentrated and purified by columnchromatography to give Int-G. Triphenyphosphine, tetra-n-butylammoniumbromide (TBAB) and dilute hydrochloric acid is added to Int-G in anorganic solvent to form a mixture that is stirred at room temperature.The mixture is concentrated and the residue purified by columnchromatography to give Int-H. Int-H is reacted with Int-A and potassiumcarbonate and the mixture is stirred overnight with heating undernitrogen atmosphere. The mixture is concentrated under vacuum andpurified by prep-TLC to give Int-E. Int-E is then reacted with (NH₄)₂CO₃and potassium cyanide (KCN) in aqueous alcohol overnight. The reactionmixture is evaporated to remove the solvent and then extracted. Theorganic layer is dried and evaporated, and the residue purified bycolumn chromatography to obtain compounds according to embodiments ofthe application.

A solution of Int-A and Int-B in an organic solvent is prepared andsodium hydroxide is added to the solution to form a reaction mixture.The reaction mixture is stirred overnight then mixed with water and anorganic solvent and extracted. The organic layer is dried and evaporatedunder high vacuum and the residue is purified by column chromatographyto give Int-C. Ethane-1,2-diol and TsOH are added to a mixture of Int-Cin organic solvent and the mixture is heated under reflux under nitrogenatmosphere. The mixture is concentrated under reduced pressure and theresidue purified by column chromatograph to give Int-I. Int-I is reactedwith Int-D, triphenylphosphine, and diethyl azodicarboxylate (DEAD) atroom temperature under stirring. The reaction is quenched with water andextracted. The organic layer is dried, concentrated under reducedpressure, and the residue is purified by column chromatography to giveInt-J. A mixture of Int-J in acid is stirred under heating. The reactionmixture is cooled to room temperature and concentrated under reducedpressure. The residue is added with saturated sodium bicarbonate andextracted. The organic layer is washed, dried, and concentrated underreduced pressure to give Int-E. Int-E is then reacted with (NH₄)₂CO₃ andpotassium cyanide (KCN) in aqueous alcohol overnight. The reactionmixture is evaporated to remove the solvent and then extracted. Theorganic layer is dried and evaporated, and the residue purified bycolumn chromatography to obtain compounds according to embodiments ofthe application.

LDA is added to a mixture of Int-K at −78° C. under nitrogen atmosphereand the mixture is stirred for 1 hour. Then, Int-L is added dropwise andthe mixture is stirred for 1 hour. The reaction is quenched with asaturated aqueous solution of ammonium chloride and extracted. Theorganic layer is washed, dried, concentrated under vacuum and theresidue purified by column chromatography to give Int-M. Int-M isoxidized to give Int-N. Pd(dba)₂ is added to a mixture of Int-N, Int-H(prepared as described above in General Scheme 2), DPPF and DIEA. Themixture is stirred under heating, then filtered and extracted. Theorganic phase is dried, concentrated under reduced pressure and theresidue purified by column chromatograph to provide Int-P. Int-P is thenreacted with (NH₄)₂CO₃ and potassium cyanide (KCN) in aqueous alcoholovernight. The reaction mixture is evaporated to remove the solvent andthen extracted. The organic layer is dried and evaporated, and theresidue purified by column chromatography to obtain compounds accordingto embodiments of the application.

To a solution of Int-D in organic solvent, Int-Q, triphenylphosphine,and DEAD are added at 0°. The mixture is warmed to room temperature andstirred. Then the mixture is quenched with water and extracted. Theorganic layer is washed, dried, concentrated under vacuum and theresidue purified by column chromatography to give Int-R. To a solutionof Int-R in organic solvent, Int-A and potassium carbonate are added.The mixture is stirred under heating then hydrochloric acid is added toadjust the pH to 6-7. The mixture is extracted and the organic layer iswashed, dried, concentrated under reduced pressure, and the residuepurified by column chromatography to give Int-S. Int-S is then reactedwith (NH₄)₂CO₃ and potassium cyanide (KCN) in aqueous alcohol overnight.The reaction mixture is evaporated to remove the solvent and thenextracted. The organic layer is dried and evaporated, and the residuepurified by column chromatography to obtain compounds according toembodiments of the application.

To a solution of Int-A in organic solvent, Int-T and potassium carbonateare added at room temperature under nitrogen atmosphere. The mixture isstirred at room temperature and after TLC analysis of the mixture showsconversion to the desired product, the mixture is diluted with water,extracted, and the organic layer is washed, dried, concentrated underreduced pressure, and the residue purified by column chromatography toobtain Int-U. TsOH is added to a solution of Int-U in organic solvent.After several minutes of stirring, a solution of ethane-1,2-diol inorganic solvent is added dropwise. The mixture is stirred under heatingand then poured over saturated sodium bicarbonate solution andextracted. The organic phase is dried, concentrated under reducedpressure and purified by column chromatography to obtain Int-V. Int-V isreduced with LAH and the reaction is quenched, extracted and the organiclayer dried and concentrated under reduced pressure. The residue ispurified by column chromatography to give Int-Y. SOCl₂ is added to amixture of Int-Y in organic solvent at 0° C. After stirring for severalhours, the pH is adjusted to pH 7 and the mixture is extracted. Theorganic layer is dried, concentrated under reduced pressure and theresidue purified by column chromatography to give Int-X. Int-X isreacted with Int-Y and potassium carbonate at room temperature undernitrogen atmosphere. The mixture is diluted with water and extracted,and the organic layer is washed, dried, concentrated under reducedpressure, and the residue purified by column chromatography to provideInt-Z. A mixture of Int-Z in acid is stirred under heating. The reactionmixture is cooled to room temperature and concentrated under reducedpressure. The residue is added with saturated sodium bicarbonate andextracted. The organic layer is washed, dried, and concentrated underreduced pressure to give Int-A1. Int-A1 is then reacted with (NH₄)₂CO₃and potassium cyanide (KCN) in aqueous alcohol overnight. The reactionmixture is evaporated to remove the solvent and then extracted. Theorganic layer is dried and evaporated, and the residue purified bycolumn chromatography to obtain compounds according to embodiments ofthe application.

Triethylamine and DMAP are added to a solution of Int-B1 and BOC₂O inorganic solvent and the mixture is stirred at room temperature. Themixture is quenched, extracted, and the organic phase washed, dried,concentrated under reduced pressure and the residue purified by columnchromatography to obtain Int-C1. Int-C1 is reacted with Int-A andpotassium carbonate at room temperature. The mixture is diluted withwater, extracted, and the organic phase washed, dried, concentratedunder reduced pressure and the residue purified by column chromatographyto obtain Int-D1. TsOH is added to a stirred solution of Int-D1 inorganic solvent. After several minutes of stirring, a solution ofethane-1,2-diol in organic solvent is added dropwise. The mixture isstirred under heating and then poured over saturated sodium bicarbonatesolution and extracted. The organic phase is dried, concentrated underreduced pressure and purified by column chromatography to obtain Int-E1.Sodium hydride is added to a solution of Int-E1 and Int-D. The mixtureis diluted with water and extracted, and the organic layer is washed,dried, concentrated under reduced pressure, and the residue purified bycolumn chromatography to provide Int-F1. A mixture of Int-F1 in acid isstirred under heating. The reaction mixture is cooled to roomtemperature and concentrated under reduced pressure. The residue isadded with saturated sodium bicarbonate and extracted. The organic layeris washed, dried, and concentrated under reduced pressure to giveInt-G1. Int-G1 is then reacted with (NH₄)₂CO₃ and potassium cyanide(KCN) in aqueous alcohol overnight. The reaction mixture is evaporatedto remove the solvent and then extracted. The organic layer is dried andevaporated, and the residue purified by column chromatography to obtaincompounds according to embodiments of the application.

Hydrochloric acid (HCl), sulfuric acid (H₂SO₄) and NaNO₂ aresuccessively added to a solution of Int-B1 at 0° C. and the mixture isstirred. Then, urea is added. After stirring for several minutes, asolution of KI in water is added dropwise and the mixture is stirred at0° C. The mixture is extracted, the organic layer is dried andevaporated, and the residue purified by column chromatography to obtainInt-H1. A mixture of Int-H1 in alcohol is stirred at room temperaturefor several hours, then the mixture is concentrated under reducedpressure, extracted and purified by column chromatography to obtainInt-I1. Int-A and potassium carbonate are added to a solution of Int-I1and the mixture is stirred at room temperature. Then, water is added andthe mixture is extracted. The organic layer is dried and evaporated, andthe residue purified by column chromatography to obtain Int-J1. To asolution of Int-J1 and Int-K1 in triethylamine is added palladiumcomplex suitable for palladium-catalyzed coupling reactions and CuIunder nitrogen atmosphere. The mixture is stirred at room temperatureand then quenched with saturated ammonium chloride solution. The mixtureis extracted, and the organic layer is washed, dried, and concentratedunder reduced pressure to give Int-L1. Pd/C is added to a solution ofInt-L1 in alcohol and the mixture is stirred under hydrogen atmosphereat room temperature. The mixture is filtered, and the filtrate isconcentrated to give Int-M1. Int-M1 is then reacted with (NH₄)₂CO₃ andpotassium cyanide (KCN) in aqueous alcohol overnight. The reactionmixture is evaporated to remove the solvent and then extracted. Theorganic layer is dried and evaporated, and the residue purified bycolumn chromatography to obtain compounds according to embodiments ofthe application.

To a solution of Int-N1, sodium hydroxide and Int-B are added and themixture is stirred overnight. The reaction mixture is extracted, theorganic layer is dried, and the residue purified by flash chromatographyto give Int-O1. To a solution of Int-O1, potassium carbonate and Int-Dare added and the mixture is stirred at room temperature. The mixture isextracted, the organic layer washed, dried, concentrated under reducedpressure, and the residue purified by column chromatography to giveInt-P1. To a solution of Int-P1 in anhydrous solvent is added DIBAL-H at0° C. The mixture is quenched, extracted, the organic layer washed,dried, concentrated under reduced pressure, and the residue purified bycolumn chromatography to give Int-Q1. Int-Q1 is oxidized to give Int-R₁.Int-R₁ is then reacted with (NH₄)₂CO₃ and potassium cyanide (KCN) inaqueous alcohol overnight. The reaction mixture is evaporated to removethe solvent and then extracted. The organic layer is dried andevaporated, and the residue purified by column chromatography to obtaincompounds according to embodiments of the application.

Nitrogen atoms of the hydantoin moiety of compounds of the applicationcan be alkylated by reacting compounds prepared according to any one ofthe above General Schemes with sodium hydride and alkyl iodide (e.g.,CH₃I). Compounds in which one of X, Y, and Z is S(O) or SO₂ can beprepared by reacting compounds prepared according to any one of theabove General Schemes with m-CPBA.

Pharmaceutically acceptable salts of compounds of the application can besynthesized from the parent compound containing an acidic or basicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate acid or base in water or inan organic solvent, or in a mixture of the two. Examples of suitableorganic solvents include, but are not limited to, ether, ethyl acetate,ethanol, isopropanol, or acetonitrile.

Compositions

Another aspect of the application relates to a pharmaceuticalcomposition comprising a compound of the application as describedherein, or a tautomer, stereoisomer, pharmaceutically acceptable salt,or solvate thereof.

Compositions of the application can also comprise a pharmaceuticallyacceptable carrier. A pharmaceutically acceptable carrier is non-toxicand should not interfere with the efficacy of the active ingredient.Pharmaceutically acceptable carriers can include one or more excipientssuch as binders, disintegrants, swelling agents, suspending agents,emulsifying agents, wetting agents, lubricants, flavorants, sweeteners,preservatives, dyes, solubilizers and coatings. The precise nature ofthe carrier or other material can depend on the route of administration,e.g., intramuscular, intradermal, subcutaneous, oral, intravenous,cutaneous, intramucosal (e.g., gut), intranasal or intraperitonealroutes. For liquid injectable preparations, for example, suspensions andsolutions, suitable carriers and additives include water, glycols, oils,alcohols, preservatives, coloring agents and the like. For solid oralpreparations, for example, powders, capsules, caplets, gelcaps andtablets, suitable carriers and additives include starches, sugars,diluents, granulating agents, lubricants, binders, disintegrating agentsand the like. For nasal sprays/inhalant mixtures, the aqueoussolution/suspension can comprise water, glycols, oils, emollients,stabilizers, wetting agents, preservatives, aromatics, flavors, and thelike as suitable carriers and additives.

Compositions of the application can be formulated in any matter suitablefor administration to a subject to facilitate administration and improveefficacy, including, but not limited to, oral (enteral) administrationand parenteral injections. The parenteral injections include intravenousinjection or infusion, subcutaneous injection, intradermal injection,and intramuscular injection. Compositions of the application can also beformulated for other routes of administration including transmucosal,ocular, rectal, long acting implantation, sublingual administration,under the tongue, from oral mucosa bypassing the portal circulation,inhalation, or intranasal.

In particular embodiments, compositions are formulated for oraladministration.

Yet another aspect of the application relates to a method of preparing apharmaceutical composition comprising combining a compound of theapplication or a tautomer, stereoisomer, pharmaceutically acceptablesalt, or solvate thereof, with at least one pharmaceutically acceptablecarrier. Pharmaceutical compositions can be prepared by any method knownin the art in view of the present disclosure, and one of ordinary skillin the art will be familiar with such techniques used to preparepharmaceutical compositions. For example, a pharmaceutical compositionaccording to the application can be prepared by mixing a compound of theapplication with one or more pharmaceutically acceptable carriersaccording to conventional pharmaceutical compounding techniques,including but not limited to, conventional admixing, dissolving,granulating, emulsifying, encapsulating, entrapping or lyophilizingprocesses.

Methods of Use

The application also provides methods of inhibiting a matrixmetalloproteinase (MMP), and treating diseases mediated by MMPs usingthe compounds of the application and pharmaceutical compositions of theapplication.

Matrix metalloproteinases (MMPs), also known as matrixins, are a groupof enzymes that in concert are responsible for the degradation of mostextracellular matrix proteins during organogenesis, growth and normaltissue turnover. MMPs are calcium-dependent zinc-containingendopeptidases, and belong to a larger family of proteases known as themetzincin superfamily. MMPs are capable of degrading extracellularmatrix proteins, but can also process a number of bioactive molecules,and known to be involved in, e.g., cleavage of cell surface receptors,release of apoptotic ligands, and chemokine/cytokine inactivation. MMPsare also thought to play a major role in cell behaviors such as cellproliferation, migration (adhesion/dispersion), differentiation,angiogenesis, apoptosis, and host defense. The MMPs are inhibited byspecific endogenous tissue inhibitor of metalloproteinases (TIMPs),which comprise a family of four protease inhibitors: TIMP-1, TIMP-2,TIMP-3, and TIMP-4. Examples of MMPs include, but are not limited to,MMP-1(Interstitial collagenase), MMP-2 (gelatinase-A), MMP-3(stromelysin 1), MMP-7 (matrilysin), MMP-8 (neutrophil collagenase),MMP-9 (gelatinase-B), MMP-10 (stromelysin 2), MMP-11 (stromelysin 3),MMP-12 (macrophage elastase), MMP-13 (collagenase 3), MMP-14 (MT1-MMP),etc.

In a preferred embodiment, compounds of the application are capable ofinhibiting microphage elastase (MMP-12) and/or treating diseasesmediated by MMP-12. MMP-12, also known as macrophage metalloelastase(MME) or macrophage elastase (ME), is encoded by the MMP12 gene inhumans. In other embodiments, compounds of the application are capableof selectively inhibiting MMP-12. The terms “selective,” “selectivity,”and “selectively” when used with reference to binding or inhibiting theactivity of a particular MMP, mean that a compound binds or inhibits theactivity of a particular MMP to a greater extent than said compoundbinds or inhibits the activity of other MMPs. For example, a compoundthat has selectivity for MMP-12 inhibits the activity of MMP-12 to agreater extent than other MMPs, e.g., MMP-1, MMP-2, MMP-3, MMP-7, MMP-8,MMP-9, MMP-10, MMP-13, MMP-14, etc.

According to embodiments of the application, a compound that isselective for MMP-12 inhibits the activity of MMP-12 by at least about10-fold, 100-fold, or 1000-fold greater than one or more other MMPs, andpreferably inhibits the activity of MMP-12 by at least about 1000-foldgreater than at least one other MMP, such as MMP-1 or MMP-7.

The application also provides methods of treating a disease mediated byMMP-12. According to embodiments of the invention, a method of treatinga disease mediated by MMP-12 comprises administering to the subject atherapeutically effective amount of a compound of the application or atautomer, stereoisomer, pharmaceutically acceptable salt, or solvatethereof, or a pharmaceutical composition of the application.

As used herein, the terms “treat,” “treating,” and “treatment” are allintended to refer to an amelioration or reversal of at least onemeasurable physical parameter related to a disease mediated by MMP-12,which is not necessarily discernible in the subject, but can bediscernible in the subject. The terms “treat,” “treating,” and“treatment,” can also refer to causing regression, preventing theprogression, or at least slowing down the progression of a diseasemediated by MMP-12. In a particular embodiment, “treat,” “treating,” and“treatment” refer to an alleviation, prevention of the development oronset, or reduction in the duration of one or more symptoms associatedwith a disease mediated by MMP-12. In a particular embodiment, “treat,”“treating,” and “treatment” refer to prevention of the recurrence of adisease mediated by MMP-12. In a particular embodiment, “treat,”“treating,” and “treatment” refer to an increase in the survival of asubject having a disease mediated by MMP-12. In a particular embodiment,“treat,” “treating,” and “treatment” refer to elimination of a diseasemediated by MMP-12 in the subject.

As used herein, “a therapeutically effective amount” means an amount ofa composition or compound that elicits a biological or medicinalresponse in a tissue system or subject that is being sought by aresearcher, veterinarian, medical doctor or other conditions, which caninclude alleviation of the symptoms of the disease or disorder beingtreated. A therapeutically effective amount can vary depending upon avariety of factors, such as the physical condition of the subject, age,weight, health, etc.; and the particular disease to be treated. Atherapeutically effective amount can readily be determined by one ofordinary skill in the art in view of the present disclosure.

In particular embodiments of the application, a therapeuticallyeffective amount refers to the amount of a composition or compound ofthe application which is sufficient to inhibit MMP-12 or treat a diseasemediated by MMP-12. Diseases mediated by MMP-12 that can be treatedaccording to the methods of the application include, but are not limitedto, asthma, chronic obstructive pulmonary disease (COPD), emphysema,acute lung injury, idiopathic pulmonary fibrosis (IPF), sarcoidosis,systemic sclerosis, liver fibrosis, nonalcoholic steatohepatitis (NASH),arthritis, cancer, heart disease, inflammatory bowel disease (IBD),acute kidney injury (AKI), chronic kidney disease (CKD), Alportsyndrome, and nephritis.

EMBODIMENTS

Embodiment 1 is a compound of formula (I-b):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof, wherein:

-   -   ring B is an optionally substituted aryl or optionally        substituted heteroaryl;    -   ring C is an optionally substituted aryl or optionally        substituted heteoraryl;    -   ring D is an optionally substituted aryl or optionally        substituted heteroaryl;    -   each of X, Y and Z is independently selected from the group        consisting of CH₂, O, NR_(x) and S(O)_(q), wherein R_(x) is        hydrogen or alkyl;    -   R₁ is hydrogen or alkyl;    -   R₄ is hydrogen or alkyl;    -   R₅ is hydrogen; and    -   q is 0, 1, or 2,    -   provided that ring B is not furanyl.

Embodiment 2 is a compound of formula (I):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof, wherein:

-   -   ring B is an optionally substituted aryl or optionally        substituted heteroaryl;    -   ring C is aryl or heteroaryl;    -   ring D is aryl or heteroaryl;    -   each of X, Y, and Z is independently selected from the group        consisting of O, CH₂, NR_(x), and S(O)_(q), wherein R_(x) is        hydrogen or alkyl;    -   R₁ is hydrogen or alkyl;    -   each R₂ is independently selected from the group consisting of        hydrogen, alkyl, halogen, hydroxyl, haloalkyl, alkoxy,        alkylthio, amine, amide, alkylamine, aminoalkyl, cyano,        hydroxyalkyl, —(CH₂)_(p)C(O)OR₆, and —(CH₂)_(p)OC(O)R₆;    -   each R₃ is independently selected from the group consisting of        hydrogen, alkyl and halogen;    -   R₄ is hydrogen or alkyl;    -   R₅ is hydrogen;    -   each R₆ is independently selected from the group consisting of        hydrogen and alkyl, wherein the alkyl is unsubstituted or        substituted with one or more groups independently selected from        the group consisting of amine, hydroxyl, halogen, and alkoxy;    -   m is 1, 2, 3, or 4;    -   n is 1, 2, 3, 4, or 5;    -   p is 0, 1, 2, 3, 4, or 5; and    -   q is 0, 1, or 2    -   provided that ring B is not furanyl.

Embodiment 3 is the compound of embodiment 1 or embodiment 2, whereinring B is a five or six membered monocyclic heteroaryl having 1-2heteroatoms independently selected from N, S, and O.

Embodiment 4 is the compound of any one of embodiments 1-3, wherein ringB is pyridinyl, thiophenyl, imidazolyl, pyrazolyl, or oxazolyl.

Embodiment 5 is the compound of embodiment 4, wherein ring B ispyridinyl.

Embodiment 6 is the compound of embodiment 5, wherein the compound is acompound of formula (II).

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof,wherein each of the variables is as defined in the compound of formula(I).

Embodiment 7 is the compound of embodiment 5, wherein the compound is acompound of formula (II-a), (II-b), (II-c), or (II-d):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof,wherein each of the variables is as defined in the compound of formula(I).

Embodiment 8 is the compound of embodiment 4, wherein ring B isthiophenyl.

Embodiment 9 is the compound of embodiment 8, wherein the compound is acompound of formula (IV):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof,wherein each of the variables is as defined in the compound of formula(I).

Embodiment 10 is the compound of embodiment 4, wherein ring B isimidazolyl.

Embodiment 11 is the compound of embodiment 10, wherein the compound isa compound of formula (Va) or (Vb):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof,wherein each of the variables is as defined in the compound of formula(I).

Embodiment 12 is the compound of embodiment 4, wherein ring B ispyrazolyl.

Embodiment 13 is the compound of embodiment 12, wherein the compound isa compound of formula (VI):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof,wherein each of the variables is as defined in the compound of formula(I).

Embodiment 14 is the compound of embodiment 4, wherein ring B isoxazolyl.

Embodiment 15 is the compound of embodiment 14, wherein the compound isa compound of formula (VII):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof,wherein each of the variables is as defined in the compound of formula(I).

Embodiment 16 is the compound of embodiment 15, wherein the compound isa compound of formula (VII-a) or (VII-b):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof,wherein each of the variables is as defined in the compound of formula(I).

Embodiment 17 is the compound of any one of embodiments 1 to 6, whereinring C is phenyl.

Embodiment 18 is the compound of any one of embodiments 1 to 6, whereinring C is pyridinyl.

Embodiment 19 is the compound of any one of embodiments 2 to 18, whereinR₃ is selected from the group consisting of hydrogen, methyl, fluoro,and chloro.

Embodiment 20 is the compound of any one of embodiments 1 to 19, whereinring D is pyridinyl or phenyl.

Embodiment 21 is the compound of any one of embodiments 2 to 20, whereinR₂ is selected from the group consisting of methyl, —CH₂OH, hydroxyl,—OC(O)CH(NH₂)CH(CH₃)₂, —COOH, —CH₂OC(O)CH(NH₂)CH(CH₃)₂, —C(O)NH₂,—C(O)NH(CH₃), and C₁₋₄alkoxy.

Embodiment 22 is the compound of any one of embodiments 1 to 21, whereinring D is:

Embodiment 23 is the compound of any one of embodiments 1 to 22, whereinR₄ is hydrogen.

Embodiment 24 is the compound of any one of embodiments 1 to 22, whereinR₄ is alkyl.

Embodiment 25 is the compound of embodiment 24, wherein R₄ is methyl.

Embodiment 26 is the compound of any one of embodiments 1 to 25, whereinR₅ is methyl.

Embodiment 27 is the compound of any one of embodiments 1 to 25, whereinR₅ is hydrogen.

Embodiment 28 is the compound of any one of embodiments 1 to 27, whereinR₁ is a C₁₋₄ alkyl.

Embodiment 29 is the compound of embodiment 28, wherein R₁ is methyl orethyl.

Embodiment 30 is the compound of any one of embodiments 1 to 27, whereinR₁ is hydrogen.

Embodiment 31 is the compound of any one of embodiments 1 to 30, whereinX is S, Y is O, and Z is CH₂.

Embodiment 32 is a compound of formula (I-a):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof,wherein:

-   -   ring B is 5- or -6-membered heteroaryl;    -   Z is CH or N;    -   each of R₁ and R₄ is alkyl or hydrogen;    -   R₅ is hydrogen;    -   R₂ is selected from the group consisting of alkyl, amide,        hydroxyl, alkoxy, and hydroxylalkyl; and    -   X and Y are each independently selected from S and O.

Embodiment 33 is the compound of embodiment 32, wherein ring B ispyridinyl, thiophenyl, imidazolyl, pyrazolyl, or oxazolyl.

Embodiment 34 is the compound of embodiment 32 or embodiment 33, whereinR₁ is hydrogen.

Embodiment 35 is the compound of embodiment 32 or embodiment 33, whereinR₁ is C₁₋₄ alkyl.

Embodiment 36 is the compound of embodiment 35, wherein R₁ is methyl orethyl.

Embodiment 37 is the compound of any one of embodiments 32 to 36,wherein R₄ is hydrogen.

Embodiment 38 is a pharmaceutical composition comprising the compound ofany one of embodiments 1-37, and at least one pharmaceuticallyacceptable carrier.

Embodiment 39 is a method of inhibiting macrophage elastase (MMP-12) ina subject in need thereof, the method comprising administering to thesubject the pharmaceutical composition of embodiment 38.

Embodiment 40 is a method of treating a disease mediated by macrophageelastase (MMP-12) in a subject in need thereof, the method comprisingadministering to the subject the pharmaceutical composition ofembodiment 38.

Embodiment 41 is the method of embodiment 40, wherein the disease isselected from the group consisting of asthma, chronic obstructivepulmonary disease (COPD), emphysema, acute lung injury, idiopathicpulmonary fibrosis (IPF), sarcoidosis, systemic sclerosis, liverfibrosis, nonalcoholic steatohepatitis (NASH), arthritis, cancer, heartdisease, inflammatory bowel disease (IBD), acute kidney injury (AKI),chronic kidney disease (CKD), Alport syndrome, and nephritis.

Embodiment 42 is the compound of any one of embodiments 1-37, or thepharmaceutical composition of embodiment 38 for use in inhibitingmacrophage elastase (MMP-12).

Embodiment 43 is the compound of any one of embodiments 1-37, or thepharmaceutical composition of embodiment 38 for use treating a diseasemediated by macrophage elastase (MMP-12).

Embodiment 44 is the compound or composition for use of embodiment 43,wherein the disease is selected from the group consisting of asthma,chronic obstructive pulmonary disease (COPD), emphysema, acute lunginjury, idiopathic pulmonary fibrosis (IPF), sarcoidosis, systemicsclerosis, liver fibrosis, nonalcoholic steatohepatitis (NASH),arthritis, cancer, heart disease, inflammatory bowel disease (IBD),acute kidney injury (AKI), chronic kidney disease (CKD), Alportsyndrome, and nephritis.

Embodiment 45 is use of the compound of any one of embodiments 1-37, orthe pharmaceutical composition of embodiment 38 in the manufacture of amedicament for inhibiting macrophage elastase (MMP-12).

Embodiment 46 is use of the compound of any one of embodiments 1-37, orthe pharmaceutical composition of embodiment 38 in the manufacture of amedicament for treating a disease mediated by macrophage elastase(MMP-12).

Embodiment 47 is use of embodiment 46, wherein the disease is selectedfrom the group consisting of asthma, chronic obstructive pulmonarydisease (COPD), emphysema, acute lung injury, idiopathic pulmonaryfibrosis (IPF), sarcoidosis, systemic sclerosis, liver fibrosis,nonalcoholic steatohepatitis (NASH), arthritis, cancer, heart disease,inflammatory bowel disease (IBD), acute kidney injury (AKI), chronickidney disease (CKD), Alport syndrome, and nephritis.

Embodiment 48 is a method of preparing the pharmaceutical composition ofembodiment 38, comprising combining the compound or a pharmaceuticallyacceptable salt thereof with at least one pharmaceutically acceptablecarrier.

EXAMPLES

The following examples of the application are to further illustrate thenature of the application. It should be understood that the followingexamples do not limit the application and the scope of the applicationis to be determined by the appended claims.

Methods of Synthesis

Unless indicated otherwise, the abbreviations for chemical reagents andsynthesis conditions have their ordinary meaning known in the art asfollows:

-   -   “LDA” refers to lithium diisopropyl amide;    -   “EA” refers to ethyl acetate;    -   “PE” refers to petroleum ether;    -   “r.t.” and “rt” refer to room temperature;    -   “THF” refers to tetrahydrofuran;    -   “DEAD” refers to diethyl azodicarboxylate;    -   “TBAB” refers to tetrabutylammonium bromide;    -   “DCM” refers to dichloromethane;    -   “HOBT” refers to hydroxybenzotriazole;    -   “LAH” refers to lithium aluminum hydride;    -   “TLC” refers to thin layer chromatography;    -   “Prep-TLC” refers to preparatory thin layer chromatography;    -   “TMS-I” refers to trimethylsilyl iodide;    -   “Hex” refers to hexanes;    -   “DMF” refers to dimethylformamide;    -   “h” refers to hours;    -   “EDCI” refers to 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide;    -   “DMAP” refers to 4-Dimethylaminopyridine;    -   “Prep-HPLC” refers to preparative high performance liquid        chromatography;    -   “DHP” refers to dihydropyran;    -   “DPPF” refers to 1,1′-Bis(diphenylphosphino)ferrocene; and    -   “DIEA” refers to diisopropylethylamine.

Preparation of Key Intermediate TI-1 for the Synthesis of CompoundsTC-1, TC-2, TC-3, TC-4, TC-5, TC-6, TC-7 and TC-8

To a solution of 3-bromothiophene-2-carbaldehyde (10 g, 52.5 mmol) and4-mercaptophenol (6.3 g, 50 mmol) in THE (255 mL) was added NaOH (0.06g, 1.5 mmol). The reaction mixture was stirred overnight at rt. Theresidue was added with water and EA, and extracted with EA twice. Thecombined organic layer was dried with MgSO₄, and evaporated under highvacuum to give a yellow solid. The residue was purified by flashchromatography with DCM/MeOH (DCM/MeOH=1:50) to give TI-1a as a lightyellow solid (9.2 g, 75%).

Synthesis of Compounds TC-1, TC-2, TC-3, TC-4, TC-5, and TC-6

TI-1: R₃ = Pr TI-2: R₃ = Et TI-3: R₃ = i-Pr

TI-4

TI-5

TI-6

TC-1: R₃ = Pr TC-2: R₃ = Et TC-3: R₃ = i-Pr

TC-4

TC-5

TC-6

A solution of 3-a (0.2 g, 1.65 mmol), TI-1a (0.40 g, 1.7 mmol), andK₂CO₃ (0.7 g) in ACN was stirred at r.t. overnight. The reaction wasmonitored by TLC (EA/Hex=2/7), to determine when the benzyl bromide spotwas disappeared. The reaction mixture was added with EA and water, andextracted EA twice. The combined organic layer was dried with MgSO₄. Theresidue was purified by flash chromatography with EA/Hexane(EA/Hexane=1:3) to give intermediate TI-1 as a light yellow solid (0.41g, 55%). Intermediates TI-2, TI-3, TI-4, TI-5 and TI-6 were synthesizedaccording to the same procedure except that the starting material 3-12was replaced with 3-14, 3-15, 3-16 or 3-17, accordingly.

To a solution of TI-1 (0.42 g, 1.18 mmol) in EtOH/H₂O (10 mL/5 mL) wasadded (NH₄)₂CO₃ (1.71 g, 17.8 mmol) and KCN (0.15 g, 0.98 mmol). Thereaction mixture was stirred at r.t. overnight. The solution wasevaporated to remove most of the solvent. The mixture was added withwater and then extracted with EA twice. The organic layers werecombined, dried with MgSO₄ and evaporated. The residue was purified byflash chromatography with EA/Hexane (EA/Hexane=1:1) to give TC-1 as alight yellow solid (0.28 g, 38%). Compounds TI-2, TI-3, TI-4, TI-5 andTI-6 were synthesized using the same procedure except that intermediateTI-1 was replaced with intermediates TI-2, TI-3, TI-4, TI-5 or TI-6,accordingly.

Preparation of Compound TC-7

A solution of 3-18a (0.23 g, 0.76 mmol), TI-1a (0.15 g, 0.64 mmol), andK₂CO₃ (0.35 g, 2.56 mmol) in ACN (4 mL) was stirred at r.t. overnight.The reaction mixture was added with water and EA, and extracted with EAtwice. The combined organic layer was dried with MgSO₄, and evaporatedunder high vacuum. The residue was purified by flash chromatography withEA/Hex (EA/Hex=1:10 to 1:4) to yield TI-7a as a yellow solid (0.17 g,50%)

To a solution of TI-7a (1.03 g) in DCM (25 mL) was added TFA (1 mL)dropwise at r.t. The reaction mixture was stirred overnight, then thesolvent and TFA were removed to obtain a brown oil. The brown oil wasadded with NaHCO₃ and MeOH. Then the solvent was removed again. Theresidue was purified by flash chromatography with EA/Hex (EA/Hex=1:4) toyield TI-7b as a white solid (0.14 g).

To a solution of TI-1b (0.14 g, 0.41 mmol) in EtOH/H₂O (5 mL/2.5 mL) wasadded (NH₄)₂CO₃ (0.24 g, 2.46 mmol) and KCN (32 mg, 0.41 mmol). Thereaction mixture was stirred at r.t. overnight. The solution wasevaporated to remove most of the solvent. The mixture was added withwater and EA, and then extracted with EA twice. The organic layers werecombined, dried with MgSO₄ and evaporated under high vacuum. The residuewas purified by flash chromatography with DCM/MeOH (DCM/MeOH=20:1) toyield TC-7 as an oily compound (51 mg).

Preparation of Compound TC-8

A solution of TI-1a (0.9 g, 3.81 mmol, 1 eq.),4-Chloromethyl-2-methylpyridine (mg, 1.19 mmol, 1 eq.), and K₂CO₃ (1.58g, 3 eq.) in 70 ml of ACN was stirred and heated to 50° C. The mixturewas monitored by TLC. The solvent was removed by rotary evaporator. Theresidue was added with EA and water, and the water layer was quenchedwith EA two times. The crude product was purified with silica gel(DCM/EA=1/4) to yield TI-8 as a pale-yellow solid (1.02 g, 76%).

To a solution of TI-8 (200 mg, 0.4 mmol, 1 eq.), KCN (0.057 mg, 1.5 eq.)and ammonium carbonate (0.844 g, 15 eq.) in 10 ml of EtOH/D.I. water(2/1) was added to the mixture. The mixture was monitored by TLC. Thesolvent was removed by rotary evaporator. The residue was added with EAand water, and the water layer was quenched with EA two times. The crudeproduct was purified on silica gel (DCM/MeOH=30/2) to yield TC-8 as ayellow solid (45 mg, 18%).

General Scheme: Preparation of Intermediate 4a-1

Synthesis of Intermediate FI-5

A mixture of compound 2a (68 g, 538.9 mmol, 1.0 eq) in DMSO (500 mL) wasstirred at 80° C. overnight under nitrogen atmosphere. Then the mixturewas diluted with H₂O (1000 mL) and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated to give compound FI-5 (67 g, 99%).

Synthesis of Intermediate FI-6

-   -   A mixture of compound FI-5 (5 g, 19.97 mmol, 1.0 eq), compound        3b (7.39 g, 39.95 mmol, 2 eq) and K₂CO₃ (11.04 g, 79.89 mmol,        4.0 eq) in acetone (100 mL) was stirred at 60° C. for 4 h under        nitrogen atmosphere. Then the mixture was diluted with H₂O (1000        mL) and extracted with ethyl acetate. The organic layer was        washed with brine, dried over Na₂SO₄, filtered and concentrated.        The residue was purified by column chromatography on a silica        gel (PE/EA, 10:1) to give compound FI-6 (8.7 g, 97%).

Synthesis of Compound 4a-1

To a mixture of compound FI-6 (10.7 g, 23.33 mmol, 1.0 eq) in THE (100mL) was added PPh₃ (6.11 g, 23.33 mmol, 1 eq), TBAB (15.04 g, 46.66mmol, 2 eq) and 5% HCl (5 mL). The mixture was stirred at rt for 12 hunder nitrogen atmosphere. Then the mixture was concentrated. Theresidue was purified by column chromatography on a silica gel (PE/EA,2:1) to give compound 4a-1 (6.6 g, 56%).

Preparation of Compound PC-1

To a mixture of compound 4a-1 (0.5 g, 2.17 mmol, 1.0 eq) in ACN (15 mL)was added compound 2-chloronicotinaldehyde (0.307 g, 2.17 mmol, 1.0 eq)and K₂CO₃ (0.906 g, 6.52 mmol, 3.0 eq). The mixture was stirred at 85°C. overnight under nitrogen atmosphere. Then the mixture wasconcentrated under vacuum. The residue was purified by Prep-TLC to givecompound PI-1 (500 mg, 69%).

To a mixture of compound PI-1 (450 mg, 1.34 mmol, 1.0 eq) in MeOH (30mL) was added KCN (174 mg, 2.68 mmol, 2.0 eq) and (NH₄)₂CO₃ (516 mg, 5.3mmol, 4.0 eq). The mixture was stirred at 40° C. overnight undernitrogen atmosphere. Then the mixture was concentrated in vacuum. Theresidue was purified by Prep-TLC to give compound PC-1 (44 mg, 10%).

Preparation of Compounds PC-2, PC-3 and PC-4

Compounds PC-2, PC-3, and PC-4 were synthesized using the same procedureas the synthesis of PC-1 except that the starting material2-chloronicotinaldehyde PS-1 was replaced with 4-chloro-nicotinaldehydePS-2, 3-fluoropicolinaldehyde PS-3, or 3-chloroisonicotinaldehyde PS-4,accordingly.

Preparation of Key Intermediate PI-a.1

To a mixture of 4-chloronicotinaldehyde (2.2 g, 15.54 mmol, 1.0 eq) and4-mercaptophenol (2.94 g, 23.31 mmol, 1.5 eq) in THF (20 mL) was addedNaH (1.24 g, 31.08 mmol, 2.0 eq) at 0° C. and the mixture was stirred atrt overnight under nitrogen atmosphere. Then the mixture wasconcentrated to half solvent and then 2.0 N HCl was added to adjust thepH=6, and filtered to give compound PI-a.1 (950 mg, 26%), which was usedin the next step without further purification.

Preparation of Compounds PC-7, PC-8 and PC-9

PI-7a

PI-8a

PI-9a

PI-7b

PI-8b

PI-9b

PC-7

PC-8

PC-9

To a mixture of compound PI-a.1 (3.0 g, 12.99 mmol, 1.0 eq) in toluene(100 mL) was successively added ethane-1,2-diol (1.6 g, 260 mmol, 20 eq)and TsOH (0.112 g, 0.65 mmol, 0.05 eq). The mixture was heated underreflux for 12 h under nitrogen atmosphere. Then the mixture wasconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel (PE/EA, 2:1) to give compound PI-b.1 (2.9g, 82%).

To a solution of compound PI-b.1 (200 mg, 0.727 mmol, 1.0 eq) in THE (10mL) was successively added 1,4-phenylenedimethanol (50 mg, 3.64 mmol,5.0 eq), PPh₃ (381 mg, 1.454 mmol, 2.0 eq) and DEAD (253 mg, 1.454 mmol,2.0 eq) at 0° C. The mixture was allowed to warm to room temperature andstirred for 16 h. Then the mixture was quenched with H₂O (10 mL) andextracted with ethyl acetate (2×10 mL). The combined organic layers weredried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel to givecompound PI-7a (200 mg, 70%).

A mixture of compound PI-7a (140 mg, 0.354 mmol, 1.0 eq) in HCl/THF (2.0M, 3 mL/3 mL) was stirred at 70° C. for 3 h. The reaction mixture wascooled to room temperature and concentrated under reduced pressure. Theresidue was added with saturated NaHCO₃ solution to adjust the pH=8 andextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure togive compound PI-7b (130 mg, 100%), which was used in the next stepwithout further purification.

To a mixture of compound PI-7b (150 mg, 0.427 mmol, 1.0 eq) in MeOH (5mL) was added KCN (55 mg, 0.854 mmol, 2.0 eq) and (NH₄)₂CO₃ (164 mg,1.71 mmol, 4.0 eq). The mixture was stirred at room temperature for 12h. Then the mixture was diluted with water and extracted with ethylacetate. The organic phase was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified byPrep-TLC to give compound PC-7 (38 mg, 21%) as a white solid.

Compounds PC-8 and PC-9 were synthesized by the same procedure exceptthat 1,4-phenylenedimethanol was replaced with 1,3-phenylenedimethanolor 1,2-phenylenedimethanol accordingly.

Preparation of Compound PC-10

A mixture of 3-(hydroxymethyl)phenol (180 mL, 1.9 mol, 4.0 eq) in Ac₂O(360 mL, 9.54 mol, 21.2 eq) was stirred at 60° C. for 1 h under nitrogenatmosphere. The reaction mixture was cooled to room temperature, thenKOH (42.3 g, 0.45 mol, 1.0 eq) was added. Then the mixture was stirredat room temperature for 16 h. After the mixture was extracted with EA(3×150 mL) and water, the combined organic layers were washed with H₂O(3×100 mL) and saturated NaHCO₃ solution (2×100 mL), dried over Na₂SO₄and concentrated under reduced pressure to give compound PI-10a (60 g,26%).

To a solution of compound PI-b.1 (300 mg, 1.09 mmol, 1.0 eq) in THE (10mL) was successively added compound PI-10a (905 mg, 5.45 mmol, 5.0 eq),PPh₃ (572 mg, 2.18 mmol, 2.0 eq) and DEAD (380 mg, 2.18 mmol, 2.0 eq) at0° C. The mixture was allowed to warm to room temperature and stirredfor 16 h. Then the mixture was quenched with H₂O (10 mL) and extractedwith ethyl acetate (2×10 mL). The combined organic layers were driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography on a silica gel to givecompound PI-10b (200 mg, 44%).

A mixture of compound PI-10b (200 mg, 0.473 mmol, 1.0 eq) in HCl/THF(2.0 M, 3 mL/3 mL) was stirred at 70° C. for 3 h. The reaction mixturewas cooled to room temperature and concentrated under reduced pressure.The residue was added with saturated NaHCO₃ solution to adjust the pH=8and extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to give compound PI-10c (150 mg, 91%), which was used in thenext step without further purification.

To a mixture of compound PI-10c (150 mg, 0.427 mmol, 1.0 eq) in MeOH (5mL) was added KCN (55 mg, 0.854 mmol, 2.0 eq) and (NH₄)₂CO₃ (164 mg,1.71 mmol, 4.0 eq). The mixture was stirred at room temperature for 12h. Then the mixture was diluted with water and extracted with ethylacetate. The organic phase was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified byPrep-TLC to give compound PC-10 (55 mg, 30%) as a white solid.

Preparation of Compound PC-11

To a solution of compound PC-8 (1.0 g, 2.37 mmol, 1.0 eq) in DCM (50 mL)was successively added (tert-butoxycarbonyl)-D-valine (1.02 g, 2.61 mol,1.1 eq), EDCI (0.53 g, 2.84 mol, 1.2 eq) and DMAP (0.056 g, 0.47 mol,0.2 eq). The mixture was stirred at 25° C. for 24 h. Then the mixturewas concentrated under reduced pressure. The residue was purified bycolumn chromatography on silica gel (DCM/MeOH, 10:1) to give compoundPI-11 (496 mg, 35%) as a yellow solid.

To a solution of compound PI-11 (0.5 g, 0.8 mmol, 1.0 eq) in EA (20 mL)was added HCl (4.5 M in EA, 20 mL). The mixture was stirred at roomtemperature for 12 h. Then the mixture was concentrated under reducedpressure to give PC-11 (430 mg, 96%) as a white solid.

Preparation of Key Intermediate PI-a.2

To a mixture of 3-fluoroisonicotinaldehyde (2.9 g, 23.2 mmol, 1.0 eq) inDMF (150 mL) was successively added 4-mercaptophenol (5.85 g, 46.4 mmol,2.0 eq) and K₂CO₃ (12.8 g, 92.8 mmol, 4.0 eq). The mixture was stirredat room temperature for 16 h under nitrogen atmosphere. Then 3 M HCl wasadded to adjust the pH=6 to 7. The mixture was extracted with EA and theorganic layer was washed with brine, dried over Na₂SO₄, concentratedunder reduced pressure. The residue was purified by columnchromatography on a silica gel to give compound PI-a.2 (1.6 g, 30%).

Preparation of Compounds PC-12, PC-13 and PC-14

PI-14a

PI-13a

PI-12A

PI-14b

PI-13b

PI-12b

PC-14

PC-13

PC-12

To a mixture of compound PI-a.2 (2.3 g, 9.96 mmol, 1.0 eq) in toluene(100 mL) was successively added ethane-1,2-diol (1.2 g, 19.9 mmol, 20eq) and TsOH (86 mg, 0.498 mmol, 0.05 eq). The mixture was heated underreflux for 12 h under nitrogen atmosphere. Then the mixture wasconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel to give compound PI-b.2 (2.2 g, 81%).

To a solution of compound PI-b.2 (1.5 g, 5.45 mmol, 1.0 eq) in THE (50mL) was successively added 1,4-phenylenedimethanol (2.63 g, 19 mmol, 3.5eq), PPh₃ (2.86 g, 10.9 mmol, 2.0 eq) and DEAD (1.9 g, 10.9 mmol, 2.0eq) at 0° C. The mixture was allowed to warm to room temperature andstirred for 16 h. Then the mixture was quenched with H₂O (50 mL) andextracted with ethyl acetate (2×50 mL). The combined organic layers weredried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel to givecompound PI-14a (1.5 g, 70%).

A mixture of compound PI-14a (500 mg, 1.266 mmol, 1.0 eq) in HCl/THF(3.0 M, 35 mL/35 mL) was stirred at 70° C. for 12 h. The reactionmixture was cooled to room temperature and concentrated under reducedpressure. The residue was added with saturated NaHCO₃ solution to adjustthe pH=8 and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by silica gel chromatography to givecompound PI-14b (280 mg, 63%).

To a mixture of compound PI-14b (150 mg, 0.427 mmol, 1.0 eq) in EtOH (5mL) and H₂O (2.5 mL) was added KCN (42 mg, 0.641 mmol, 1.5 eq) and(NH₄)₂CO₃ (410 mg, 4.27 mmol, 10.0 eq). The mixture was stirred at 50°C. for 5 h. Then the mixture was diluted with water and extracted withethyl acetate. The organic phase was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified byPrep-TLC to give compound PC-14 (70 mg, 25%) as a white solid.

Compounds PC-12 and PC-13 were synthesized by the same procedure exceptthat 1,2-phenylenedimethanol was replaced with 1,3-phenylenedimethanolor 1,4-phenylenedimethanol, accordingly.

Preparation of Compound PC-15

To a solution of compound PI-b.2 (500 mg, 1.82 mmol, 1.0 eq) in THE (20mL) was successively added compound PI-10a (1.1 g, 6.37 mmol, 3.5 eq),PPh₃ (954 mg, 3.64 mmol, 2.0 eq) and DEAD (634 mg, 3.64 mmol, 2.0 eq) at0° C. The mixture was allowed to warm to room temperature and stirredfor 16 h. Then the mixture was quenched with H₂O (10 mL) and extractedwith ethyl acetate (2×10 mL). The combined organic layers were driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel to givecompound PI-15a (460 mg, 60%).

A mixture of compound PI-15a (1 g, 2.364 mmol, 1.0 eq) in HCl/THF (3.0M, 25 mL/25 mL) was stirred at 70° C. for 16 h. The reaction mixture wascooled to room temperature and concentrated under reduced pressure. Theresidue was added with saturated NaHCO₃ solution to adjust the pH=8 andextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography to give compoundPI-15b (200 mg, 25%).

To a mixture of compound PI-15b (200 mg, 0.593 mmol, 1.0 eq) in EtOH (6mL) and H₂O (6 mL) was added KCN (58 mg, 0.89 mmol, 1.5 eq) and(NH₄)₂CO₃ (570 mg, 5.93 mmol, 10.0 eq). The mixture was stirred at 50°C. for 4 h. Then the mixture was diluted with water and extracted withethyl acetate. The organic phase was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified byPrep-HPLC to give compound PC-15 (58 mg, 24%) as a white solid.

Preparation of Compounds PC-16 and PC-17

To a solution of compound PI-b.2 (1.2 g, 4.363 mmol, 1.0 eq) in THE (20mL) was successively added (2-methylpyridin-4-yl)methanol (2.68 g, 21.8mmol, 5.0 eq), PPh₃ (2.29 g, 8.73 mmol, 2.0 eq) and DEAD (1.5 g, 8.73mmol, 2.0 eq) at 0° C. The mixture was allowed to warm to roomtemperature and stirred for 16 h. Then the mixture was quenched with H₂O(50 mL) and extracted with ethyl acetate (2×50 mL). The combined organiclayers were dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by column chromatography on silicagel to give compound PI-16a (1.4 g, 84%).

A mixture of compound PI-16a (1.4 g, 3.684 mmol, 1.0 eq) in HCl/THF (2.0M, 30 mL/30 mL) was stirred at 70° C. for 3 h. The reaction mixture wascooled to room temperature and concentrated under reduced pressure. Theresidue was added with saturated NaHCO₃ solution to adjust the pH=8 andextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure togive compound PI-16b (760 mg, 61%), which was used in the next stepwithout further purification.

To a mixture of compound PI-16b (760 mg, 2.262 mmol, 1.0 eq) in MeOH (10mL) was added KCN (294 mg, 4.524 mmol, 2.0 eq) and (NH₄)₂CO₃ (869 mg,9.048 mmol, 4.0 eq). The mixture was stirred at room temperature for 12h. Then the mixture was diluted with water and extracted with ethylacetate. The organic phase was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by silicagel chromatography to give compound PC-16 (130 mg, 14%) as a whitesolid.

Compound PC-17 was synthesized by the same procedure as the synthesis ofcompound PC-16 except that (2-methylpyridin-4-yl)methanol was replacedwith (5-methylpyridin-3-yl)methanol.

Preparation of Compounds PC-18 and PC-19

Compounds PC-18 and PC-19 were synthesized by the same procedure as thesynthesis of PC-16 except that PI-b.2 was replaced with PI-b.1 asstarting material.

Preparation of Compounds PC-20 and PC-21

To a solution of compound PI-b.1 (1.2 g, 4.36 mmol, 1.0 eq) in THE (10mL) was successively added compound PS-4a (2.0 g, 8.73 mmol, 2.0 eq),PPh₃ (3.4 g, 13.0 mmol, 3.0 eq) and DEAD (2.3 g, 13.0 mmol, 3.0 eq) at0° C. The mixture was allowed to warm to room temperature and stirredfor 20 h. Then the mixture was quenched with H₂O (100 mL) and extractedwith ethyl acetate (2×100 mL). The combined organic layers were driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel (PE/EA, 1:1)to give compound PI-20a (2.0 g, 95%) as a white solid.

A mixture of compound PI-20a (500 mg, 1.02 mmol, 1.0 eq) and HCl (3 M inH₂O, 10 mL) in THE (15 mL) was stirred at 70° C. for 12 h. The reactionmixture was cooled to room temperature and concentrated under reducedpressure. The residue was added with saturated NaHCO₃ solution to adjustthe pH=8 and filtered to give compound PI-20b (400 mg, 100%), which wasused in the next step without further purification.

To a solution of compound PI-20b (220 mg, 0.601 mmol, 1.0 eq) and KCN(117 mg, 1.803 mmol, 3.0 eq) in EtOH (12 mL) and H₂O (6 mL) was added(NH₄)₂CO₃ (577 mg, 6.01 mmol, 10.0 eq). The mixture was stirred at 50°C. for 5 h. The mixture was added with 0.5 M HCl to adjust the pH=1˜2and stirred for 10 min. Then saturated NaHCO₃ solution was added toadjust the pH=6 to 7. The mixture was stirred for 1 h and filtered. Theresidue was purified by Prep-HPLC to give PC-20 (160 mg, 61.3%) as awhite solid.

Preparation of Intermediates of PS-4a and PS-4b

A mixture of formic acid (180 mL, 1.9 mol, 4.0 eq) in Ac₂O (360 mL, 9.54mol, 21.2 eq) was stirred at 60° C. for 1 h under nitrogen atmosphere.The reaction mixture was cooled to room temperature, then PhOH (42.3 g,0.45 mol, 1.0 eq) and NaHCO₃ (76.5 g, 0.91 mol, 2.0 eq) were added. Thenthe mixture was stirred at room temperature for 16 h. After the mixturewas extracted with EA (3×150 mL) and water, the combined organic layerswere washed with H₂O (3×100 mL) and saturated NaHCO₃ solution (2×100mL), dried over Na₂SO₄ and concentrated under reduced pressure to givecompound PS-4.1 (60 g, 26%).

To a mixture of (2-bromopyridin-4-yl)methanol (25 g, 133.69 mmol, 1.0eq) and DHP (22.46 g, 267.38 mmol, 2.0 eq) in DCM (290 mL) was addedTsOH (2.23 g, 13.37 mmol, 0.1 eq). The mixture was stirred at roomtemperature for 15 h. TLC analysis of the reaction mixture showed fullconversion to the desired product. Then the mixture was diluted with H₂O(100 mL) and extracted with dichloromethane. The organic layer waswashed with brine (100 mL), dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel (PE/EA, 4:1) to give compound PS-4a.1 (34.1g, 94.1%).

To a mixture of compound PS-4a.1 (30 g, 110.7 mmol, 1.0 eq), compoundPS-4.1 (33.7 g, 276.75 mmol, 2.5 eq), Et₃N (28 g, 276.75 mmol, 2.5 eq)and P(t-Bu)₃HBF₄ (3.85 g, 13.284 mmol, 0.12 eq) in ACN (700 mL) wasadded Pd(OAc)₂ (743.9 mg, 3.321 mmol, 0.03 eq) under nitrogenatmosphere. The mixture was stirred at 80° C. for 15 h. Then the mixturewas filtered and the filtrate was concentrated under reduced pressure.The residue was purified by column chromatography on silica gel (PE/EA,1:1) to give compound PS-4a.2 (11 g, 32%).

A mixture of compound PS-4a.2 (25 g, 79.8 mmol, 1.0 eq) and HCl (2 M inH₂O, 55 mL) in THE (55 mL) was stirred at room temperature for 3 h. TLCanalysis of the reaction mixture showed full conversion to the desiredproduct. Then the mixture was dried over Na₂SO₄ and concentrated underreduced pressure. The residue was purified by column chromatography on asilica gel (PE/EA, 2:1) to give compound PS-4a (8 g, 44%).

The intermediate PS-4b was prepared by the same procedure ofsynthesizing PS-4a except that (2-bromopyridin-4-yl)methanol wasreplaced with (5-bromopyridin-3-yl)methanol as starting material.

Preparation of Compound PC22

To a mixture of 4-chloropyridine (100 g, 0.667 mol, 1.0 eq) in dry THE(1 L) was quickly added LDA (2 M in THF, 733.26 mL, 1.467 mol, 2.2 eq)at −78° C. under nitrogen atmosphere. The mixture was stirred at −78° C.for 1 h. Then propionaldehyde (74.1 g, 0.999 mol, 1.5 eq) was addeddropwise and the mixture was stirred for 1 h. TLC analysis of thereaction mixture showed full conversion to the desired product. Thereaction was quenched with a saturated aqueous solution of NH₄Cl andextracted with EA (3×500 mL). The organic layer was washed with brineand water, dried over Na₂SO₄ and concentrated under vacuum. The residuewas purified by column chromatography on silica gel (PE: EA, 3:1) togive compound PI-22a (45 g, 48%).

To a mixture of PI-22a (26.3 g, 0.154 mol, 1.0 eq) in acetone (300 mL)was added CrO₃ (30.8 g, 0.308 mol, 2.0 eq). The mixture was stirred atroom temperature for 5 h. Then the mixture was filtered and the filtratewas concentrated under reduced pressure. The residue was purified bysilica gel chromatography to afford compound PI-22b (16.0 g, 62%).

To a mixture of PI-22b (850 mg, 5.03 mmol, 1.0 eq), compound 4a-1 (1.27g, 5.53 mmol, 1.1 eq), DPPF (42 mg, 0.503 mmol, 0.1 eq) and DIEA (973mg, 7.55 mmol, 1.5 eq) in toluene (10 mL) was added Pd(dba)₂ (202 mg,0.352 mmol, 0.07 eq) under nitrogen atmosphere. The mixture was stirredat 110° C. for 16 h. Then the mixture was filtered and extracted withwater and ethyl acetate. The organic phase was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby silica gel chromatography to afford compound PI-22c (550 mg, 30%).

To a mixture of PI-22c (550 mg, 1.515 mmol, 1.0 eq) in EtOH (8 mL) andH₂O (2 mL) was added KCN (295 mg, 4.55 mmol, 3.0 eq) and (NH₄)₂CO₃ (720mg, 7.576 mmol, 5.0 eq). The mixture was stirred at 50° C. for 3 d. Thenthe mixture was diluted with water and extracted with ethyl acetate. Theorganic phase was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue was purified by silica gel chromatographyto give compound PC-22 (50 mg, 7%) as a white solid.

Preparation of Compound PC-23

To a mixture of 3-(methoxycarbonyl)benzoic acid (5 g, 27.78 mmol, 1.0eq) in dry THE (20 mL) was added BH₃/THF (1 M in THF, 55 mL, 55.5 mmol,2.0 eq) at 0° C. The mixture was stirred at 30° C. for 16 h undernitrogen atmosphere. Then the mixture was diluted with water andextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel to givecompound PI-23a (4.2 g, 91%).

To a solution of PI-23a (4.1 g, 24.7 mmol, 1.0 eq) in THE (100 mL) wassuccessively added 1,4-hydroquinone (5.4 g, 49.4 mmol, 2.0 eq), PPh₃(13.0 g, 49.4 mmol, 2.0 eq) and DEAD (8.6 g, 49.4 mmol, 2.0 eq) at 0° C.The mixture was allowed to warm to room temperature and stirred for 16h. Then the mixture was quenched with H₂O (100 mL) and extracted withethyl acetate (2×100 mL). The combined organic layers were dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by column chromatography on a silica gel (PE/EA, 2:1) togive compound PI-23b (2.1 g, 33%).

To a solution of compound PI-23b (2.1 g, 8.14 mmol, 1.0 eq) in DMF (15mL) were added 4-chloronicotinaldehyde (1.73 g, 12.2 mmol, 1.5 eq) andK₂CO₃ (2.25 g, 16.28 mmol, 2.0 eq). The mixture was stirred at 80° C.for 4 h under nitrogen atmosphere. Then 3 M HCl was added to adjust thepH=6 to 7. The mixture was extracted with EA and the organic layer waswashed with brine, dried over Na₂SO₄, concentrated under reducedpressure. The residue was purified by column chromatography on a silicagel (PE/EA, 3:1) to give compound PI-23c (900 mg, 31%).

To a mixture of compound PI-23c (200 mg, 0.551 mmol, 1.0 eq) in MeOH (5mL) was added KCN (72 mg, 1.1 mmol, 2.0 eq) and (NH₄)₂CO₃ (211 mg, 2.2mmol, 4.0 eq). The mixture was stirred at room temperature for 12 h.Then the mixture was diluted with water and extracted with ethylacetate. The organic phase was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified byPrep-TLC to give compound PI-23d (100 mg, 42%).

To a mixture of PI-23d (100 mg, 0.23 mmol, 1.0 eq) in MeOH (5 mL) wasadded NaOH (80 mg, 2.0 mmol, 10.0 eq). The mixture was stirred at roomtemperature for 3 h. The mixture was concentrated to halve the solventand then 1 N HCl was added to adjust the pH=5. The mixture was filteredto give PC-23 (47 mg, 48%).

Preparation of Compound PC-24

Compound PC-24 was synthesized by the same procedure as the synthesis ofPC-22 except that the starting material PI-b.1 was replaced with PI-b.2.

Preparation of Compound PC-25

To a mixture of PI-23c (2.4 g, 6.61 mmol, 1.0 eq) in toluene (40 mL) wassuccessively added ethane-1,2-diol (3.7 g, 60 mmol, 10 eq) and TsOH(56.5 mg, 0.33 mmol, 0.05 eq). The mixture was heated under reflux for12 h under nitrogen atmosphere. Then the mixture was concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel (PE/EA, 2:1) to give compound PI-25a (2.3 g, 85%).

To a mixture of PI-25a (2.3 g, 25.65 mmol, 1.0 eq) in dry THE (100 mL)was added DIBAL-H (1.0 M in toluene, 14.1 mL, 14.1 mmol, 2.5 eq)dropwise at 0° C. under nitrogen atmosphere. The mixture was stirred at0° C. for 1 h. Then Na₂SO₄·10 H₂O (6.6 g, 20.5 mmol, 0.8 eq) was addeddropwise and the mixture was stirred for 0.5 h. The reaction wasquenched with a saturated aqueous solution of NH₄Cl and extracted withEtOAc (3×100 mL). The organic layer was washed with brine and water,dried over Na₂SO₄ and concentrated under vacuum. The residue waspurified by column chromatography on silica gel (PE: EA, 3:1) to givecompound PI-25b (1.1 g, 51%).

A mixture of PI-25b (1.1 g, 2.902 mmol, 1.0 eq) in HCl/THF (2.0 M, 20mL/20 mL) was stirred at 70° C. for 3 h. The reaction mixture was cooledto room temperature and concentrated under reduced pressure. The residuewas added with saturated NaHCO₃ solution to adjust the pH=8 andextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure togive compound PI-25c (1.0 g, 100%), which was used in the next stepwithout further purification.

To a mixture of compound PI-25c (1.0 g, 2.98 mmol, 1.0 eq) in MeOH (20mL) was added KCN (38 mg, 5.96 mmol, 2.0 eq) and (NH₄)₂CO₃ (1.14 g,11.92 mmol, 4.0 eq). The mixture was stirred at room temperature for 12h. Then the mixture was diluted with water and extracted with ethylacetate. The organic phase was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified byPrep-TLC to give compound PC-25 (215 mg, 18%) as a white solid.

Preparation of Compounds PC-26 and PC-27

To a mixture of 1-(bromomethyl)-3-methylbenzene (5.0 g, 27 mmol, 1.0 eq)in DMF (150 mL) was successively added 1,4-hydroquinone (5.94 g, 54mmol, 2.0 eq) and K₂CO₃ (14.9 g, 108 mmol, 4.0 eq). The mixture wasstirred at 80° C. for 3 h under nitrogen atmosphere. Then 3 M HCl wasadded to adjust the pH=6 to 7. The mixture was extracted with EA and theorganic layer was washed with brine, dried over Na₂SO₄, and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel (PE/EA, 3:1) to give compound PI-26a (2.6g, 45%).

To a mixture of PI-26a (1.0 g, 4.67 mmol, 1.0 eq) in DMF (15 mL) wassuccessively added 4-chloronicotinaldehyde (0.99 g, 7 mmol, 1.5 eq) andK₂CO₃ (1.5 g, 9.34 mmol, 2.0 eq). The mixture was stirred at 80° C. for3.5 h under nitrogen atmosphere. TLC analysis of the reaction mixtureshowed full conversion to the desired product. Then the mixture wasdiluted with H₂O (100 mL) and extracted with EA (3×100 mL). The combinedorganic layers were washed with a saturated aqueous solution of NH₄Cl(3×100 mL), brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel (PE/EA, 1:1) to give compound PI-26b (480 mg, 32%).

To a solution of compound PI-26b (480 mg, 1.5 mmol, 1.0 eq) in MeOH (10mL) was added (NH₄)₂CO₃ (578 mg, 6.01 mmol, 4.0 eq) and KCN (195 mg, 3mmol, 2.0 eq). The mixture was stirred at 45° C. for 16 h. The reactionwas added with 3 M HCl to adjust the pH=1 to 2 and stirred at roomtemperature for 1 h, then a saturated aqueous solution of NaHCO₃ wasadded to adjust the pH=6 to 7 and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified byPrep-TLC to give PC-26 (208.1 mg, 44%) as a white solid. Compound PC-27was synthesized in the same fashion expect that the starting material1-(bromomethyl)-3-methylbenzene was replaced with4-(bromomethyl)-2-methylpyridine.

Preparation of Compounds PC-28 and PC-29

To a mixture of 3-(chloromethyl)benzoic acid (1.7 g, 9.965 mmol, 1.0 eq)in DCM (50 mL) was added (COCl)₂ (1.7 mL, 19.931 mmol, 2.0 eq) drop wiseat 0° C. The mixture was stirred for 1 h while the solution becameclarified. Then the mixture was concentrated under reduced pressure. Toa mixture of the residue in DCM was added a solution of NH₃ in THE at−10° C. The mixture was stirred for 0.5 h and then concentrated underreduced pressure to give compound PI-28a (1.3 g, 77%)

To a mixture of compound PI-28a (1.0 g, 5.92 mmol, 1.0 eq) in DMF (50mL) was successively added compound PI-a.1 (1.36 g, 5.92 mmol, 1.0 eq)and K₂CO₃ (2.45 g, 17.76 mmol, 3.0 eq). The mixture was stirred at roomtemperature for 16 h under nitrogen atmosphere. Then 3 M HCl was addedto adjust the pH=6 to 7. The mixture was extracted with EA and theorganic layer was washed with brine, dried over Na₂SO₄, and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel to give compound PI-28b (850 mg, 40%).

To a mixture of compound PI-28b (850 mg, 2.33 mmol, 1.0 eq) in MeOH (10mL) was added KCN (303 mg, 4.66 mmol, 2.0 eq) and (NH₄)₂CO₃ (904 mg,9.33 mmol, 4.0 eq). The mixture was stirred at 45° C. for 16 h. Then themixture was diluted with water and extracted with ethyl acetate. Theorganic phase was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue was purified by Prep-TLC to give compoundPC-28 (500 mg, 49%) as a white solid.

Compound PC-29 was synthesized in the same procedure except that NH₃ wasreplaced with MeNH₂.

Preparation of Compounds PC-30, PC-31, PC-32 and PC-33

To a mixture of compound 3-8 (750 mg, 3.876 mmol, 1.0 eq) in DMF (15 mL)was successively added compound PI-a.1 (895 mg, 3.876 mmol, 1.0 eq) andK₂CO₃ (2.14 g, 15.5 mmol, 4.0 eq). The mixture was stirred at roomtemperature for 16 h under nitrogen atmosphere. Then 3 M HCl was addedto adjust the pH=6 to 7. The mixture was extracted with EA and theorganic layer was washed with brine, dried over Na₂SO₄, and concentratedunder reduced pressure. The residue was purified by columnchromatography on a silica gel (PE/EA, 1:1) to give compound PI-30 (610mg, 36%).

To a solution of compound PI-30 (500 mg, 1.419 mmol, 1.0 eq) in MeOH (6mL) was added (NH₄)₂CO₃ (545 mg, 5.676 mmol, 4.0 eq) and KCN (185 mg,2.838 mmol, 2.0 eq). The mixture was stirred at 45° C. for 16 h. Thereaction was added with 3 M HCl to adjust the pH=1 to 2 and stirred atroom temperature for 1 h, then a saturated aqueous solution of NaHCO₃was added to adjust the pH=6 to 7 and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified byPrep-TLC to give PC-30 (350 mg, 58%) as a white solid. Compounds PC-31,PC-32 and PC-33 were synthesized in the same fashion except intermediate3-8 was replaced with 3-9, 3-11, and 3-10, accordingly.

Preparation of Compounds PC-34 and PC-36

Compounds PC-34 and PC-36 were synthesized according to the sameprocedure as the synthesis of compounds PC-28 and PC-29 except thatstarting material 3-(chloromethyl)benzoic acid was replaced with5-(chloromethyl)nicotinic acid.

Preparation of Compound PC-35

To a solution of compound PC-30 (400 mg, 0.95 mmol, 1.0 eq) in CHCl₃ (30mL) was added TMS-I (1.35 mL, 9.5 mmol, 10.0 eq). The mixture wasstirred at 55° C. for 16 h. The reaction mixture was cooled to roomtemperature and concentrated under reduced pressure. The residue waspurified by prep-TLC (EA: MeOH, 10:1) to provide compound PC-35 (350 mg,90%) as a white solid.

Preparation of Compound PC-37

Compound PC-37 was synthesized according to the same procedure as thesynthesis of compound PC-28 except that the intermediate PC-28a wasreplaced with FI-18a.

Preparation of Compound PC-38

To a mixture of methyl 3-(chloromethyl)isonicotinate (800 mg, 4.32 mmol,1.0 eq) in DMF (10 mL) was successively added compound PI-b.1 (1.19 g,4.32 mmol, 1.0 eq) and CsCO₃ (4.23 g, 12.97 mmol, 3.0 eq). The mixturewas stirred at room temperature for 16 h under nitrogen atmosphere. TLCanalysis of the reaction mixture showed full conversion to the desiredproduct. Then the mixture was diluted with H₂O (50 mL) and extractedwith EA (3×50 mL). The combined organic layers were washed with asaturated aqueous solution of NH₄Cl (3×50 mL), brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by column chromatography on a silica gel to give compoundPI-38a (300 mg, 16%).

A solution of compound PI-38a (300 mg, 0.708 mmol, 1.0 eq) in MeOH (10mL) was purged with NH₃ gas for 10 min at −78° C. The flask was sealedand the mixture was stirred at room temperature for 16 h. TLC analysisof the reaction mixture showed full conversion to the desired product.The mixture was concentrated under reduced pressure and the residue waspurified by silica gel chromatography to afford compound PI-38b (180 mg,62%).

A mixture of compound PI-38b (180 mg, 0.440 mmol, 1.0 eq) in HCl/THF(3.0 M, 2 mL/2 mL) was stirred at 70° C. for 3 h. The reaction mixturewas cooled to room temperature and concentrated under reduced pressure.The residue was added with saturated NaHCO₃ solution to adjust the pH=8and extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by prep-TLC to give compound PI-38c(100 mg, 62%).

To a solution of compound PI-38c (90 mg, 0.247 mmol, 1.0 eq) in MeOH (5mL) was added (NH₄)₂CO₃ (94 mg, 0.986 mmol, 4.0 eq) and KCN (32 mg,0.493 mmol, 2.0 eq). The mixture was stirred at 45° C. for 16 h. Thereaction was added with 3 M HCl to adjust the pH=1 to 2 and stirred atroom temperature for 1 h, then a saturated aqueous solution of NaHCO₃was added to adjust the pH=6 to 7 and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified byPrep-TLC to give PC-38 (55 mg, 51%) as a white solid.

Preparation of Compounds PC-39 and PC-40

To a solution of compound PI-b.1 (738 mg, 2.68 mmol, 1.0 eq) in THE (20mL) was successively added compound PS-4b (615 mg, 2.68 mmol, 1.0 eq),PPh₃ (1.4 g, 5.37 mmol, 2.0 eq) and DEAD (934 mg, 5.37 mmol, 2.0 eq) at0° C. The mixture was allowed to warm to room temperature and stirredfor 16 h. Then the mixture was quenched with H₂O (50 mL) and extractedwith ethyl acetate (2×50 mL). The combined organic layers were driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography on a silica gel to givecompound PI-39a (490 mg, 37%).

To a mixture of compound PI-39a (300 mg, 0.617 mmol, 1.0 eq) in dry THE(10 mL) was quickly added LAH (47 mg, 1.23 mmol, 2.0 eq) at 0° C. undernitrogen atmosphere. The mixture was stirred at 0° C. for 1 h. TLCanalysis of the reaction mixture showed full conversion to the desiredproduct. The reaction was quenched with Na₂SO₄·10 H₂O (159 mg, 0.494mmol, 0.8 eq) and the mixture was stirred for 0.5 h. Then the mixturewas filtered, and the organic layer was concentrated under vacuum. Theresidue was purified by prep-TLC to give compound PI-39b (150 mg, 61%).

A mixture of compound PI-39b (150 mg, 0.379 mmol, 1.0 eq) in HCl/THF(3.0 M, 4 mL/4 mL) was stirred at 70° C. for 16 h. The reaction mixturewas cooled to room temperature and concentrated under reduced pressure.The residue was added with saturated NaHCO₃ solution to adjust the pH=8and extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by prep-TLC to give compound PI-39c(110 mg, 82%).

To a solution of compound PI-39c (110 mg, 0.313 mmol, 1.0 eq) in MeOH (5mL) was added (NH₄)₂CO₃ (120 mg, 1.25 mmol, 4.0 eq) and KCN (40 mg,0.625 mmol, 2.0 eq). The mixture was stirred at 45° C. for 16 h. Thereaction was added with 3 M HCl to adjust the pH=1 to 2 and stirred atroom temperature for 1 h, then a saturated aqueous solution of NaHCO₃was added to adjust the pH=6 to 7 and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified byprep-TLC to give compound PC-39 (49 mg, 37%) as a white solid.

Compound PC-40 was synthesized by the same procedure except that PS-4bwas replaced with PS-4a.

Preparation of Compounds PC-41, PC-46, PC-54, and PC-55

To a mixture of compound PC-16 (250 mg, 0.616 mmol, 1.0 eq) in THF (2mL) was added CH₂N₂ (1 M in ether, 3 mL, 3.08 mmol, 5.0 eq). The mixturewas stirred at room temperature for 3 h. Then the mixture wasconcentrated under reduced pressure to give compound PC-41 (80 mg, 30%)as a white solid.

To a stirred solution of compound PC-41 (100 mg, 0.238 mmol, 1.0 eq) inDMF (2 mL) was added NaH (12 mg, 0.476 mmol, 2.0 eq) at 0° C. After 10min, CH₃I (68 mg, 0.476 mmol, 2.0 eq) was added. After additionalstirring at 0° C. for 0.5 h, the mixture was allowed to warm to roomtemperature and stirred for 12 h. The reaction mixture was quenched withwater and extracted with EA (3×50 mL). The combined organic phases weredried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by prep-TLC to afford compound PC-46 (40 mg, 37%)as a yellow solid.

To a stirred solution of compound PC-41 (300 mg, 0.714 mmol, 1.0 eq) inDMF (5 mL) was added NaH (17 mg, 0.714 mmol, 1.0 eq) at 0° C. After 10min, CH₃I (101 mg, 0.714 mmol, 1.0 eq) was added. After additionalstirring at 0° C. for 0.5 h, the mixture was allowed to warm to roomtemperature and stirred for 12 h. The reaction mixture was quenched withwater and extracted with EA (3×50 mL). The combined organic phases weredried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by prep-TLC to afford compound PC-54 (45 mg, 14%)as a white solid.

To a solution of compound PC-16 (1 g, 2.46 mmol, 1.0 eq) and1-(chloromethyl)-4-methoxybenzene (461 mg, 2.96 mmol, 1.2 eq) in DMF (10mL) was added NaI (369 mg, 2.46 mol, 1.0 eq) and K₂CO₃ (679 mg, 4.92mmol, 2.0 eq). The mixture was stirred at room temperature for 16 h.LCMS analysis of the reaction mixture showed full conversion to thedesired product. Then the mixture was diluted with water and extractedwith DCM. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by silicagel chromatography to afford compound PC-55 (130 mg, 34%) as a pinksolid.

Preparation of Compounds PC-42, PC-50 and PC-51

To a mixture of m-cresol (10 g, 92.5 mmol, 1.0 eq) and NaSCN (22.5 g,277.6 mmol, 3.0 eq) in MeOH (100 mL) was dropwise added a solution ofNaBr (9.5 g, 92.5 mmol, 1.0 eq) and Br₂ (5.7 mL, 111 mmol, 1.2 eq) inMeOH (100 mL). The mixture was stirred at rt for 14 h. TLC analysis ofthe reaction mixture showed full conversion to the desired product. Thereaction was added with water and extracted with EA (3×100 mL). Theorganic layer was washed with brine and water, dried over Na₂SO₄ andconcentrated under vacuum. The residue was purified by columnchromatography on silica gel to give compound PI-42a (5 g, 33%).

To a mixture of compound PI-42a (5.0 g, 30.3 mmol, 1.0 eq) in dry THF(50 mL) was quickly added LAH (1.72 g, 45.5 mmol, 1.5 eq) at 0° C. undernitrogen atmosphere. The mixture was stirred at rt for 3 h. TLC analysisof the reaction mixture showed full conversion to the desired product.The reaction was quenched with Na₂SO₄·10 H₂O and stirred at 0° C. for0.5 h. Then the mixture was filtered, and the organic layer concentratedunder vacuum. The residue was purified by silica gel chromatography togive compound PI-42b (2.9 g, 68%).

To a stirred solution of compound PI-42b (1.0 g, 7.1 mmol, 1.5 eq) inTHE (10 mL) was added NaH (170.4 mg, 7.1 mmol, 1.5 eq) at 0° C. After 30min, 4-chloronicotinaldehyde (667.4 mg, 4.73 mmol, 1.0 eq) was added at0° C. The mixture was allowed to warm to room temperature and stirredfor 16 h. The reaction mixture was quenched with water and extractedwith EA (3×10 mL). The combined organic phases were dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby silica gel chromatography to afford compound PI-42c (1.2 g, 100%).

To a mixture of compound PI-42c (200 mg, 0.82 mmol, 1.0 eq) and4-(chloromethyl)-2-methylpyridine (130 mg, 0.902 mmol, 1.1 eq) in DMF (2mL) was successively added K₂CO₃ (340 mg, 2.46 mmol, 3.0 eq). Themixture was stirred at 50° C. for 3 h under nitrogen atmosphere. TLCanalysis of the reaction mixture showed full conversion to the desiredproduct. Then the mixture was poured into water and extracted with EA(3×5 mL). The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel to give compoundPI-42d (150 mg, 52%).

To a solution of compound PI-42d (190 mg, 0.54 mmol, 1.0 eq) in MeOH (2mL) was added (NH₄)₂CO₃ (208.45 mg, 2.17 mmol, 4.0 eq) and KCN (70.2 mg,1.08 mmol, 2.0 eq). The mixture was stirred at 45° C. for 16 h. Thereaction was added with 3 M HCl to adjust the pH=1 to 2 and stirred atroom temperature for 1 h, then a saturated aqueous solution of NaHCO₃was added to adjust the pH=6 to 7 and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified byPrep-TLC to give compound PC-42 (200 mg, 88%) as a white solid.Compounds PC-50 and PC-51 were synthesized in the same fashion exceptthat the starting material m-cresol was replaced with 3-fluorophenol and3-chlorophenol, accordingly.

Preparation of Compounds PC-48, PC-49 and PC-52

Compounds PC-48, PC-49 and PC-52 were synthesized by the same procedureas the synthesis of PC-42 except that the starting material m-cresol wasreplaced with o-cresol, 2-chlorophenol and 2-fluorophenol, accordingly.

Preparation of Compounds PC-43 and PC-44

To a solution of 4-chloronicotinaldehyde (10 g, 70.92 mmol, 1.0 eq) inDMF (100 mL) was added 4-mercaptobenzoic acid (13.1 g, 85.11 mmol, 1.2eq) and K₂CO₃ (29.4 g, 0.213 mol, 3.0 eq) at room temperature undernitrogen atmosphere. The mixture was stirred at room temperature for 16h. TLC analysis of the reaction mixture showed full conversion to thedesired product. Then the mixture was diluted with water and extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by silica gel chromatography to afford PI-c.1 (11 g, 59%).

To a stirred solution of PI-c.1 (11 g, 42.47 mmol, 1.0 eq) in THE (100mL) was added TsOH (731 mg, 4.25 mmol, 0.1 eq). After 10 min,ethane-1,2-diol (13.1 g, 0.212 mol, 5.0 eq) in THE (50 mL) was addeddrop wise. The mixture was stirred at 110° C. for 16 h. The reactionmixture was poured over saturated NaHCO₃ solution (160 mL) and extractedwith EA (3×100 mL). The combined organic phases were dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by silica gel chromatography to afford PI-c.2 (8 g, 62%).

To a mixture of PI-c.2 (8 g, 26.40 mmol, 1.0 eq) in dry THE (100 mL) wasquickly added LAH (2 g, 52.81 mmol, 2.0 eq) at 0° C. under nitrogenatmosphere. The mixture was stirred at 0° C. for 1 h. TLC analysis ofthe reaction mixture showed full conversion to the desired product. Thereaction was quenched with Na₂SO₄·10 H₂O (6.8 g, 21.12 mmol, 0.8 eq) andthe mixture was stirred for 0.5 h. The mixture is extracted and then theorganic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue was purified by silica gel chromatographyto give PI-c.3 (4 g, 52%).

To a mixture of PI-c.3 (1 g, 3.46 mmol, 1.0 eq) in DCM (10 mL) was addedSOCl₂ (824 mg, 6.92 mmol, 2.0 eq) at 0° C. under nitrogen atmosphere.The mixture was stirred at 0° C. for 4 h. TLC analysis of the reactionmixture showed full conversion to the desired product. The reaction wasadded with NaHCO₃ (aq.) to adjust the pH >7 and extracted with DCM. Thenthe organic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue was purified by silica gel chromatographyto give PI-c.4 (1 g, 94%).

To a solution of compound PI-c.4 (500 mg, 1.63 mmol, 1.0 eq) in DMF (5mL) was added m-cresol (211 mg, 1.95 mmol, 1.2 eq) and K₂CO₃ (675 mg,4.89 mmol, 3.0 eq) at room temperature under nitrogen atmosphere. Themixture was stirred at room temperature for 16 h. TLC analysis of thereaction mixture showed full conversion to the desired product. Then themixture was diluted with water and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by silicagel chromatography to afford compound PI-43a (230 mg, 37%).

A mixture of PI-43a (230 mg, 0.607 mmol, 1.0 eq) in HCl/THF (3.0 M, 2mL/2 mL) was stirred at 70° C. for 14 h. The reaction mixture was cooledto room temperature and concentrated under reduced pressure. The residuewas added with saturated NaHCO₃ solution to adjust the pH=8 andextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography to give PI-43b (150mg, 73%).

To a solution of PI-43b (150 mg, 0.448 mmol, 1.0 eq) in MeOH (3 mL) wasadded (NH₄)₂CO₃ (172 mg, 1.79 mmol, 4.0 eq) and KCN (58 mg, 0.896 mmol,2.0 eq). The mixture was stirred at 40° C. for 12 h. The reaction wasadded with 3 M HCl to adjust the pH=1 to 2 and stirred at roomtemperature for 1 h, then a saturated aqueous solution of NaHCO₃ wasadded to adjust the pH=6 to 7 and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified byprep-TLC to give compound PC-43 (40 mg, 22%) as a white solid.

Compound PC-44 was synthesized in the same fashion except that m-cresolwas replaced with 2-methylpyridin-4-ol.

Preparation of Compound PC-45

To a mixture of 4-hydroxy-6-methylnicotinic acid (10 g, 65.4 mmol, 1.0eq) in DCM (100 mL), a solution of (COCl)₂ (12.35 g, 98.1 mmol, 1.5 eq)was added dropwise at 0° C. The mixture was stirred for 12 h. TLCanalysis of the reaction mixture showed full conversion to the desiredproduct. The reaction was dried over Na₂SO₄ and concentrated undervacuum to give crude PI-45a (10 g, crude).

A mixture of PI-45a (10 g, 52.9 mmol, 1.0 eq) in MeOH (100 mL) wasstirred at rt for 2 h. TLC analysis of the reaction mixture showed fullconversion to the desired product. The reaction was dried over Na₂SO₄and concentrated under vacuum. The residue was purified by silica gelchromatography to give crude PI-45b (12 g, 100%).

To a mixture of PI-45b (12.0 g, 64.86 mmol, 1.0 eq) in dry THF (100 mL)was quickly added LAH (3.69 g, 97.3 mmol, 1.5 eq) at 0° C. undernitrogen atmosphere. The mixture was stirred at rt for 3 h. TLC analysisof the reaction mixture showed full conversion to the desired product.The reaction was quenched with Na₂SO₄·10 H₂O and stirred at 0° C. for0.5 h. Then the mixture was filtered, and the organic layer concentratedunder vacuum. The residue was purified by silica gel chromatography togive PI-45c (6.0 g, 59%).

To a stirred solution of PI-45c (6.0 g, 38.2 mmol, 1.0 eq) in DCM (60mL) was added Dess-Martin periodinane (32.4 g, 76.4 mmol, 2.0 eq). Themixture was stirred at rt for 16 h. The reaction mixture was quenchedwith water and extracted with EA (3×60 mL). The combined organic phaseswere dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by silica gel chromatography toafford PI-45d (2.3 g, 39%).

To a mixture of PI-45d (2.3 g, 14.8 mmol, 1.0 eq) and 4-mercaptophenol(2.06 g, 16.3 mmol, 1.1 eq) in DMF (25 mL) was successively added K₂CO₃(6.14 g, 44.4 mmol, 3.0 eq). The mixture was stirred at 50° C. for 3 hunder nitrogen atmosphere. TLC analysis of the reaction mixture showedfull conversion to the desired product. Then the mixture was poured intowater and extracted with EA (3×30 mL). The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue was purified by column chromatography on asilica gel to give PI-45e (1.6 g, 44%).

To a mixture of PI-45e (1.0 g, 4.08 mmol, 1.0 eq) and4-(chloromethyl)-2-methylpyridine (633 mg, 4.48 mmol, 1.1 eq) in DMF (10mL) was successively added K₂CO₃ (1.69 g, 12.24 mmol, 3.0 eq). Themixture was stirred at 50° C. for 3 h under nitrogen atmosphere. TLCanalysis of the reaction mixture showed full conversion to the desiredproduct. Then the mixture was poured into water and extracted with EA(3×10 mL). The combined organic layers were washed with brine, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel to givePI-45f (700 mg, 49%).

To a solution of PI-45f (700 mg, 2.0 mmol, 1.0 eq) in MeOH (1 mL) wasadded (NH₄)₂CO₃ (767.8 mg, 8.0 mmol, 4.0 eq) and KCN (260 mg, 4.0 mmol,2.0 eq). The mixture was stirred at 45° C. for 16 h. The reaction wasadded with 3 M HCl to adjust the pH=1 to 2 and stirred at roomtemperature for 1 h, then a saturated aqueous solution of NaHCO₃ wasadded to adjust the pH=6 to 7 and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified byPrep-TLC to give PC-45 (512 mg, 61%) as a white solid.

Preparation of Compounds PC-47 and PC-53

Compounds PC-47 and PC-53 were synthesized by the same procedure as thesynthesis of PC-39 and PC-40 except that the starting material PI-b.1was replaced with PI-b.2.

Preparation of Compound PC-56

To a solution of 4-aminothiophenol (16 g, 127.8 mmol, 1.0 eq) and Boc₂O(55.2 g, 255.6 mmol, 2.0 eq) in DCM (200 mL) was added TEA (25.8 g,255.6 mmol, 2.0 eq) and DMAP (1.56 g, 12.78 mmol, 0.05 eq) at −0 oC. Themixture was stirred at room temperature for 16 h under nitrogenatmosphere. Then the mixture was quenched with saturated NH₄Cl solution.The mixture was extracted with ethyl acetate. The combined organicphases were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by silicagel chromatography to afford PI-56a (8.1 g, 28%).

To a solution of PI-56a (5 g, 22.19 mmol, 1.0 eq) in DMF (40 mL) wasadded 4-chloronicotinaldehyde (3.14 g, 22.19 mmol, 1.0 eq) and K₂CO₃(9.12 g, 66.57 mmol, 3.0 eq) at room temperature under nitrogenatmosphere. The mixture was stirred at room temperature for 16 h. TLCanalysis of the reaction mixture showed full conversion to the desiredproduct. Then the mixture was diluted with water and extracted withethyl acetate. The organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by silica gel chromatography to afford PI-56b (1.4 g, 19%).

To a mixture of PI-56b (0.6 g, 1.82 mmol, 1.0 eq) in toluene (50 mL) wassuccessively added ethane-1,2-diol (2.25 g, 36.3 mmol, 20 eq) and TsOH(0.02 g, 0.09 mmol, 0.05 eq). The mixture was heated under reflux for 12h under nitrogen atmosphere. Then the mixture was concentrated underreduced pressure. The residue was purified by column chromatography on asilica gel to give PI-56c (0.25 g, 36%).

To a solution of PI-56c (0.2 g, 0.53 mmol, 1.0 eq) in DMF (5 mL) wasadded compound 4-(chloromethyl)-2-methylpyridine (0.09 g, 0.64 mmol, 1.2eq) and NaH (14 mg, 0.58 mmol, 1.1 eq, 60%) at room temperature undernitrogen atmosphere. The mixture was stirred at room temperature for 16h. TLC analysis of the reaction mixture showed full conversion to thedesired product. Then the mixture was diluted with water and extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by silica gel chromatography to afford PI-56d (0.13 g,51%).

A mixture of PI-56d (250 mg, 0.52 mmol, 1.0 eq) in HCl/THF (2.0 M, 3mL/3 mL) was stirred at room temperature for 5 h. The reaction mixturewas concentrated under reduced pressure. The residue was added withsaturated NaHCO₃ solution to adjust pH=8 and extracted with ethylacetate. The organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby silica gel chromatography to afford PI-56e (110 mg, 63%).

To a solution of PI-56e (110 mg, 0.33 mmol, 1.0 eq) in MeOH (3 mL) wasadded (NH₄)₂CO₃ (126 mg, 1.31 mmol, 4.0 eq) and KCN (43 mg, 0.66 mmol,2.0 eq). The mixture was stirred at 45° C. for 16 h. The reaction wasadded with 3 M HCl to adjust pH=1˜2 and stirred at room temperature for1 h, then saturated aqueous of NaHCO₃ was added to adjust pH=7˜8 andextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by prep-TLC to give PC-56 (50 mg, 37%) as a whitesolid.

Preparation of Compound PC-57

To a solution of 4-aminothiophenol (10 g, 79.87 mmol, 1.0 eq) in H₂O (80mL) was successively added HCl (80 mL), H₂SO₄ (30 mL) and NaNO₂ (6.6 g,95.84 mmol, 1.2 eq) at 0° C. The mixture was stirred at 0° C. for 0.5 h.Then urea (0.46 g, 7.99 mmol, 0.1 eq) was added. After 15 min, thesolution of KI (26.5 g, 159.74 mmol, 2.0 eq) in H₂O (1.5 L) was dropwise added at 0° C. The mixture was stirred at 0° C. for 5 h. Then themixture was extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by silica gel chromatography toafford PI-57a (7.3 g, 39%).

A mixture of PI-57a (1.8 g, 3.83 mmol, 1.0 eq) in MeOH (40 mL) wasstirred at room temperature for 2 h. The reaction mixture wasconcentrated under reduced pressure. The residue was diluted with ethylacetate (50 mL) and washed with water, and brine. The organic layer wasdried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography to afford PI-57b (0.9g, 50%).

To a solution of PI-57b (230 mg, 1 mmol, 1.0 eq) in DMF (10 mL) wasadded 4-chloronicotinaldehyde (140 mg, 1 mmol, 1.0 eq) and K₂CO₃ (276mg, 2 mmol, 2.0 eq). The mixture was stirred at room temperature for 16h. Then water (30 mL) was added and extracted with ethyl acetate (20mL×3). The organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby silica gel chromatography to afford PI-57c (0.3 g, 88%).

To a solution of PI-57c (1 g, 2.9 mmol, 1.0 eq) and4-ethynyl-2-methylpyridine (0.41 g, 3.5 mmol, 1.2 eq) in TEA (1.19 g,0.29 mmol, 0.1 eq) was added Pd(Ph₃P)₂C1₂ (0.21 g, 0.29 mmol, 0.1 eq)and CuI (0.06 g, 0.29 mmol, 0.1 eq) under nitrogen atmosphere. Themixture was stirred at room temperature for 16 h under nitrogenatmosphere. Then the mixture was quenched with saturated NH₄Cl solution.The mixture was extracted with ethyl acetate. The combined organicphases were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by silicagel chromatography to afford PI-57d (0.8 g, 83%).

To a solution of PI-57d (0.2 g, 0.61 mmol, 1.0 eq) in methanol (10 mL)was added Pd/C (20 mg). The mixture was stirred under hydrogenatmosphere (20 psi) at room temperature for 16 h. The mixture wasfiltered, and the filtrate was concentrated to give PI-57e (170 mg, 84%)without further purification.

To a solution of PI-57e (180 mg, 0.54 mmol, 1.0 eq) in MeOH (5 mL) wasadded (NH₄)₂CO₃ (206 mg, 2.15 mmol, 4.0 eq) and KCN (70 mg, 1.08 mmol,2.0 eq). The mixture was stirred at 45° C. for 16 h. The reaction wasadded with 3 M HCl to adjust pH=1˜2 and stirred at room temperature for1 h, then saturated aqueous of NaHCO₃ was added to adjust pH=7˜8 andextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by prep-TLC to give PC-57 (60 mg, 27%) as a yellowsolid.

Preparation of Compound PC-58

A mixture of PI-56d (400 mg, 0.83 mmol, 1.0 eq) in TFA/DCM (1 mL/3 mL)was stirred at room temperature for 3 h. The reaction mixture wasconcentrated under reduced pressure. The residue was added saturatedNaHCO₃ solution to adjust pH=8 and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to give PI-58a (350 mg, 100%), whichwas used in the next step without further purification.

A mixture of PI-58a (360 mg, 0.95 mmol, 1.0 eq) in formic acid (80%, 3ml) and formaldehyde solution (40%, 1 ml) was prepared. The mixture washeated at 100° C. for 6 hours. The reaction mixture was cooled to roomtemperature and concentrated under reduced pressure. The residue wasadded with saturated NaHCO₃ solution to adjust pH=8 and extracted withethyl acetate. The organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by silica gel chromatography to afford PI-58b (210 mg,56%).

A mixture of PI-58b (210 mg, 0.53 mmol, 1.0 eq) in HCl/THF (2.0 M, 3mL/3 mL) was stirred at room temperature for 5 h. The reaction mixturewas concentrated under reduced pressure. The residue was added withsaturated NaHCO₃ solution to adjust pH=8 and extracted with ethylacetate. The organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to give PI-58c (160 mg,86%), which was used in the next step without further purification.

To a solution of PI-58c (180 mg, 0.52 mmol, 1.0 eq) in MeOH (3 mL) wasadded (NH₄)₂CO₃ (198 mg, 2.06 mmol, 4.0 eq) and KCN (67 mg, 1.03 mmol,2.0 eq). The mixture was stirred at 45° C. for 16 h. The reaction wasadded with 3 M HCl to adjust pH=1˜2 and stirred at room temperature for1 h, then a saturated aqueous solution of NaHCO₃ was added to adjustpH=7˜8 and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by silica gel chromatography to givePC-58 (118 mg, 54%) as a yellow solid.

Preparation of Compound PC-59

To a solution of compound 4-Pyridinemethanol (5 g, 45.82 mmol, 1.0 eq)and imidazole (7.97 g, 137.45 mmol, 3.0 eq) in DCM (100 mL) was addedTBSCl (13.8 g, 91.64 mmol, 2.0 eq) at 0° C. The mixture was stirred atroom temperature for 2 h. Then the mixture was quenched with saturatedNH₄Cl solution (100 mL). The mixture was extracted with ethyl acetate(50 mL×3). The combined organic phases were washed with brine, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography to afford compoundPI-59a (7.2 g, 70%).

To a solution of compound PI-59a (10 g, 44.76 mmol, 1.0 eq) in DCM (150mL) was added m-CPBA (11.58 g, 67.14 mmol, 1.5 eq) at room temperature.The mixture was stirred at room temperature for 16 h. TLC analysis ofthe reaction mixture showed full conversion to the desired product. Thenthe mixture was quenched with saturated aqueous of sodium sulfite. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by silicagel chromatography to afford compound PI-59b (8.1 g, 75%).

To a mixture of compound PI-59b (10.3 g, 43.4 mmol, 1.0 eq) in TEA (40mL) was added trimethylsilyl cyanide (13 g, 130.4 mmol, 3 eq). Themixture was heated at 90° C. for 3 h under nitrogen atmosphere. Then themixture was concentrated under reduced pressure. The residue waspurified by silica gel chromatography to give PI-59c (5.1 g, 47%).

To a solution of PI-59c (5.1 g, 20.53 mmol, 1.0 eq) in ethanol/H₂O(100/17 mL) was added NaOH (6.9 g, 172.5 mmol, 8.4 eq). The mixture wasstirred at 90° C. for 2 h. Then the mixture was cooled to roomtemperature and diluted with water (100 mL) and extracted with ethylacetate. The aqueous layer was acidified to pH=4˜5 and extracted withethyl acetate. The organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by silica gel chromatography to afford PI-59d (3.2 g, 99%).

To a solution of PI-59d (2.2 g, 14.36 mmol, 1.0 eq) in DMF (100 mL) wassuccessively added NH₄Cl (1.54 g, 28.73 mmol, 2.0 eq), HATU (5.46 g,14.36 mmol, 1.0 eq) and DIEA (5.57 g, 43.08 mmol, 3.0 eq). The mixturewas stirred at room temperature for 16 h. The reaction mixture wasdiluted with ethyl acetate (200 mL) and washed with brine, water, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography to afford PI-59e (0.6g, 27%).

To a mixture of PI-59e (0.53 g, 3.48 mmol, 1.0 eq) in DCM (50 mL) wasadded SOCl₂ (0.83 g, 6.96 mmol, 2.0 eq) drop wise at 0° C. undernitrogen atmosphere. The mixture was stirred at room temperature for 2h. The reaction mixture was diluted with DCM (50 mL) and washed withsaturated aqueous of NaHCO₃, brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford PI-59f (0.47 g, 79%).

To a solution of PI-59f (470 mg, 2.75 mmol, 1.0 eq) in DMF (20 mL) wasadded PI-a.1 (636 mg, 2.75 mmol, 1.0 eq) and K₂CO₃ (759 mg, 5.5 mmol, 2eq). The mixture was stirred at room temperature for 4 h. Then themixture was diluted with water (50 mL) and extracted with ethyl acetate(30 mL×3). The organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby silica gel chromatography to afford PI-59g (210 mg, 21%).

To a solution of PI-59g (400 mg, 1.09 mmol, 1.0 eq) in MeOH (7 mL) wasadded (NH₄)₂CO₃ (419 mg, 4.38 mmol, 4.0 eq) and KCN (141 mg, 2.19 mmol,2.0 eq). The mixture was stirred at 45° C. for 16 h. The reaction wasadded 3 M HCl to adjust pH=1˜2 and stirred at room temperature for 1 h,then a saturated aqueous solution of NaHCO₃ was added to adjust pH=7˜8and extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by silica gel chromatography to givePC-59 (52 mg, 11%) as a white solid.

Preparation of Compound PC-60

To a solution of PI-59f (470 mg, 2.75 mmol, 1.0 eq) in DMF (20 mL) wasadded PI-a.2 (636 mg, 2.75 mmol, 1.0 eq) and K₂CO₃ (759 mg, 5.5 mmol, 2eq). The mixture was stirred at room temperature for 4 h. Then themixture was diluted with water (50 mL) and extracted with ethyl acetate(30 mL×3). The organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby silica gel chromatography to afford PI-60a (230 mg, 23%).

To a solution of PI-60a (230 mg, 0.63 mmol, 1.0 eq) in MeOH (6 mL) wasadded (NH₄)₂CO₃ (241 mg, 2.51 mmol, 4.0 eq) and KCN (81 mg, 1.26 mmol,2.0 eq). The mixture was stirred at 45° C. for 16 h. The reaction wasadded 3 M HCl to adjust pH=1˜2 and stirred at room temperature for 1 h,then a saturated aqueous solution of NaHCO₃ was added to adjust pH=7˜8and extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by silica gel chromatography to givePC-60 (53 mg, 19%) as a yellow solid.

Preparation of Compound PC-61

To a solution of 5-Bromo-2-hydroxypyridine (5 g, 28.74 mmol, 1.0 eq) inDMF (100 mL) was added 4-(chloromethyl)-2-methylpyridine (4.07 g, 28.74mmol, 1.0 eq) and K₂CO₃ (7.93 g, 57.47 mmol, 2 eq). The mixture wasstirred at room temperature for 4 h. Then the mixture was diluted withwater (200 mL) and extracted with ethyl acetate (100 mL×3). The organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by silicagel chromatography to afford PI-61a (4.1 g, 51%).

To a mixture of PI-61a (1 g, 3.58 mmol, 1.0 eq),4-Methoxy-a-toluenethiol (607 mg, 3.94 mmol, 1.1 eq), xantphose (207 mg,0.36 mmol, 0.1 eq) and Cs₂CO₃ (1.75 g, 5.37 mmol, 1.5 eq) in dioxane (30mL) was added Pd₂(dba)₃ (230 mg, 0.25 mmol, 0.07 eq) under nitrogenatmosphere. The mixture was stirred at 90° C. for 12 h. Then the mixturewas filtered and extracted with water (50 mL) and ethyl acetate (30mL×3). The organic phase was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by silicagel chromatography to afford PI-61b (0.8 g, 63%).

PI-61b (1 g, 2.83 mmol, 1.0 eq) was dissolved in TFA (20 mL) and stirredat 90° C. for 16 h under nitrogen atmosphere. Then the mixture wasconcentrated under reduced pressure. The residue was purified by silicagel chromatography to give PI-61c (0.5 g, 76%).

To a solution of PI-61c (600 mg, 2.58 mmol, 1.0 eq) in THE (20 mL) wasadded NaH (103 mg, 2.58 mmol, 1 eq, 60%) at 0° C. under nitrogenatmosphere. The mixture was stirred at 0° C. for 1 h. Then4-chloronicotinaldehyde (365 mg, 2.58 mmol, 1.0 eq) was added. Themixture was stirred at room temperature for 12 h. The mixture wasdiluted with water (50 mL) and extracted with ethyl acetate (30 mL×3).The organic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by silicagel chromatography to afford PI-61d (250 mg, 29%)

To a solution of PI-61d (200 mg, 0.59 mmol, 1.0 eq) in MeOH (5 mL) wasadded (NH₄)₂CO₃ (227 mg, 2.37 mmol, 4.0 eq) and KCN (77 mg, 1.19 mmol,2.0 eq). The mixture was stirred at 45° C. for 16 h. The reaction wasadded 3 M HCl to adjust pH=1˜2 and stirred at room temperature for 1 h,then a saturated aqueous solution of NaHCO₃ was added to adjust pH=7˜8and extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by silica gel chromatography to givePC-61 (104 mg, 43%) as a white solid.

Preparation of Compound PC-62

To a solution of 4-iodophenol (2.2 g, 10 mmol, 1.0 eq) and4-ethynyl-2-methylpyridine (1.29 g, 11 mmol, 1.1 eq) in DMF (30 mL) wasadded TEA (3.2 g, 30 mmol, 3 eq), Pd(Ph₃P)₂Cl₂ (1.4 g, 2 mmol, 0.2 eq)and CuI (0.38 g, 2 mmol, 0.2 eq) under nitrogen atmosphere. The mixturewas stirred at room temperature for 3 h under nitrogen atmosphere. Thenthe mixture was quenched with saturated NH₄Cl (50 mL) solution. Themixture was extracted with ethyl acetate (30 mL×3). The combined organicphases were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by silicagel chromatography to afford PI-62a (1.05 g, 45%).

To a solution of PI-62a (0.8 g, 3.82 mmol, 1.0 eq) in DMF (40 mL) wasadded 4-chloronicotinaldehyde (0.54 g, 3.82 mmol, 1.0 eq) and K₂CO₃(1.05 g, 7.64 mmol, 2 eq). The mixture was stirred at 80° C. for 4 h.Then the mixture was diluted with water (100 mL) and extracted withethyl acetate (50 mL×3). The organic layer was washed with brine, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography to afford PI-62b (0.45g, 37%).

To a solution of PI-62b (1.0 eq) in methanol (10 mL) is added Pd/C (20mg). The mixture is stirred under hydrogen atmosphere (20 psi) at roomtemperature for 16 h. The mixture is filtered, and the filtrate isconcentrated to give PI-62c without further purification.

To a solution of PI-62c (1.0 eq) in MeOH (5 mL) is added (NH₄)₂CO₃ (4.0eq) and KCN (2.0 eq). The mixture is stirred at 45° C. for 16 h. Thereaction is added with 3 M HCl to adjust pH=1˜2 and stirred at roomtemperature for 1 h, then a saturated aqueous solution of NaHCO₃ isadded to adjust pH=7˜8 and extracted with ethyl acetate. The organiclayer is washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure to give PC-62.

Preparation of Compound PC-63

To a mixture of 4-chloropyridine (100 g, 0.667 mol, 1.0 eq) in dry THE(1 L) was quickly added LDA (2 M in THF, 733.26 mL, 1.467 mol, 2.2 eq)at −78° C. under nitrogen atmosphere. The mixture was stirred at −78° C.for 1 h. Then propionaldehyde (74.1 g, 0.999 mol, 1.5 eq) was addeddropwise and the mixture was stirred for 1 h. TLC analysis of thereaction mixture showed full conversion to the desired product. Thereaction was quenched with a saturated aqueous solution of NH₄Cl andextracted with ethyl acetate (3×500 mL). The organic layer was washedwith brine and water, dried over Na₂SO₄ and concentrated under vacuum.The residue was purified by column chromatography on silica gel (PE: EA,3:1) to give PI-63a (45 g, 48%).

To a mixture of PI-63a (26.3 g, 0.154 mol, 1.0 eq) in acetone (300 mL)was added CrO₃ (30.8 g, 0.308 mol, 2.0 eq). The mixture was stirred atroom temperature for 5 h. Then the mixture was filtered and the filtratewas concentrated under reduced pressure. The residue was purified bysilica gel chromatography to afford PI-63b (16.0 g, 62%)

To a mixture of PI-63b (1 g, 4.67 mmol, 1.0 eq) and 4-mercaptophenol(590 mg, 4.67 mmol, 1.0 eq) in DMF (50 mL) was added K₂CO₃ (1.29 g, 9.34mmol, 2 eq). The mixture was stirred at room temperature for 16 h undernitrogen atmosphere. Then the mixture was quenched with H₂O (100 mL) andextracted with ethyl acetate (50 mL×3). The combined organic phases werewashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue was purified by silica gel chromatographyto afford PI-63c (1.2 g, 99%).

To a mixture of PI-63c (500 mg, 1.93 mmol, 1.0 eq) and4-(chloromethyl)-2-methylpyridine (409 mg, 2.89 mmol, 1.5 eq) in DMF (20mL) was added K₂CO₃ (798 mg, 5.78 mmol, 3 eq). The mixture was stirredat 70° C. for 4 h under nitrogen atmosphere. Then the mixture wasquenched with H₂O (60 mL) and extracted with ethyl acetate (30 mL×3).The combined organic phases were washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby silica gel chromatography to afford PI-63d (610 mg, 87%).

To a solution of PI-63d (610 mg, 1.68 mmol, 1.0 eq) in MeOH/H₂O (12 mL,5/1) was added (NH₄)₂CO₃ (644 mg, 6.71 mmol, 4.0 eq) and KCN (218 mg,3.36 mmol, 2.0 eq). The mixture was stirred at 45° C. for 16 h. Thereaction was added with 3 M HCl to adjust pH=1˜2 and stirred at roomtemperature for 1 h, then a saturated aqueous solution of NaHCO₃ wasadded to adjust pH=7˜8 and extracted with ethyl acetate. The organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by silicagel chromatography to give PC-63 (80 mg, 11%) as a white solid.

Preparation of Compound PC-64

To a mixture of 3-Chloropyridine (100 g, 0.667 mol, 1.0 eq) in dry THE(1 L) was quickly added LDA (2 M in THF, 733.26 mL, 1.467 mol, 2.2 eq)at −78° C. under nitrogen atmosphere. The mixture was stirred at −78° C.for 1 h. Then propionaldehyde (74.1 g, 0.999 mol, 1.5 eq) was addeddropwise and the mixture was stirred for 1 h. TLC analysis of thereaction mixture showed full conversion to the desired product. Thereaction was quenched with a saturated aqueous solution of NH₄Cl andextracted with ethyl acetate (3×500 mL). The organic layer was washedwith brine and water, dried over Na₂SO₄ and concentrated under vacuum.The residue was purified by column chromatography on silica gel (PE: EA,3:1) to give PI-64a (45 g, 48%).

To a mixture of PI-64a (26.3 g, 0.154 mol, 1.0 eq) in acetone (300 mL)was added CrO₃ (30.8 g, 0.308 mol, 2.0 eq). The mixture was stirred atroom temperature for 5 h. Then the mixture was filtered and the filtratewas concentrated under reduced pressure. The residue was purified bysilica gel chromatography to afford PI-64b (16.0 g, 62%)

To a mixture of PI-64b (1 g, 4.67 mmol, 1.0 eq) and 4-mercaptophenol(590 mg, 4.67 mmol, 1.0 eq) in DMF (50 mL) was added K₂CO₃ (1.29 g, 9.34mmol, 2 eq). The mixture was stirred at room temperature for 16 h undernitrogen atmosphere. Then the mixture was quenched with H₂O (100 mL) andextracted with ethyl acetate (50 mL×3). The combined organic phases werewashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue was purified by silica gel chromatographyto afford PI-64c (1.2 g, 99%).

To a mixture of PI-64c (500 mg, 1.93 mmol, 1.0 eq) and4-(chloromethyl)-2-methylpyridine (409 mg, 2.89 mmol, 1.5 eq) in DMF (20mL) was added K₂CO₃ (798 mg, 5.78 mmol, 3 eq). The mixture was stirredat 70° C. for 4 h under nitrogen atmosphere. Then the mixture wasquenched with H₂O (60 mL) and extracted with ethyl acetate (30 mL×3).The combined organic phases were washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby silica gel chromatography to afford PI-64d (610 mg, 87%).

To a solution of PI-64d (700 mg, 1.92 mmol, 1.0 eq) in MeOH/H₂O (12 mL,5/1) was added (NH₄)₂CO₃ (637 mg, 7.68 mmol, 4.0 eq) and KCN (248 mg,3.83 mmol, 2.0 eq). The mixture was stirred at 45° C. for 16 h. Thereaction was added with 3 M HCl to adjust pH=1˜2 and stirred at roomtemperature for 1 h, then a saturated aqueous solution of NaHCO₃ wasadded to adjust pH=7˜8 and extracted with ethyl acetate. The organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by silicagel chromatography to give PC-64 (242 mg, 29%) as a white solid.

Preparation of Compounds OC-1 and OC-2

To a mixture of compound 4a-1 (0.5 g, 2.17 mmol, 1.0 eq) in ACN (15 mL)was added 2-fluorobenzaldehyde (0.271 g, 2.17 mmol, 1.0 eq) and K₂CO₃(0.906 g, 6.52 mmol, 3.0 eq). The mixture was stirred at 85° C.overnight under nitrogen atmosphere. Then the mixture was concentratedunder vacuum. The residue was purified by Prep-TLC to give compound 0I-1(490 mg, 68%).

To a mixture of compound OI-1 (200 mg, 0.6 mmol, 1.0 eq) in MeOH (10 mL)was added KCN (78 mg, 1.2 mmol, 2.0 eq) and (NH₄)₂CO₃ (230 mg, 2.4 mmol,4.0 eq). The mixture was stirred at 40° C. overnight under nitrogenatmosphere. Then the mixture was concentrated in vacuum to give compoundOC-1 (200 mg, 82%).

To a mixture of compound OC-1 (15 mg, 0.037 mmol, 1.0 eq) in dioxane (1mL) was added m-CPBA (6.4 mg, 0.037 mmol, 1.0 eq). The mixture wasstirred at room temperature for 12 h. Then the mixture was diluted withEA and washed with saturated NaHCO₃ aqueous. The organic layer wasconcentrated under reduced pressure. The residue was purified by silicagel chromatography to afford compound OC-2 (9.6 mg, 62%).

Preparation of Compounds OC-3 and OC-4

To a mixture of 4-chloronicotinaldehyde (1 g, 7.1 mmol, 1.0 eq) in MeOH(6 mL) was added KCN (0.92 mg, 14.2 mmol, 2.0 eq) and (NH₄)₂CO₃ (2.71 g,28.2 mmol, 4.0 eq). The mixture was stirred at room temperature for 12h. Then the mixture was diluted with water and extracted with ethylacetate. The organic phase was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified byPrep-TLC to give compound OI-3a (1.0 g, 66%) as a white solid.

To a mixture of OI-3a (1.0 g, 4.73 mmol, 1.0 eq) in dioxane (10 mL) wasadded m-CPBA (0.82 g, 4.73 mmol, 1.0 eq). The mixture was stirred atroom temperature for 12 h. Then the mixture was diluted with EA andwashed with a saturated NaHCO₃ aqueous solution. The organic layer wasconcentrated under reduced pressure. The residue was purified by silicagel chromatography to afford OI-3b (200 mg, 19%).

To a mixture of OI-3b (100 mg, 0.43 mmol, 1.0 eq) and compound 4a-1 (99mg, 0.43 mmol, 1 eq) in ACN (2 mL) was successively added K₂CO₃ (182 mg,1.31 mmol, 3.0 eq). The mixture was stirred at 85° C. for 12 h undernitrogen atmosphere. TLC analysis of the reaction mixture showed fullconversion to the desired product. Then the mixture was poured intowater and extracted with EA (3×5 mL). The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel to give OC-3 (23.6 mg, 13%).

To a mixture of compound OC-3 (20 mg, 0.05 mmol, 1.0 eq) in dioxane (1mL) was added m-CPBA (8.5 mg, 0.05 mmol, 1.0 eq). The mixture wasstirred at room temperature for 12 h. Then the mixture was diluted withEA and washed with a saturated NaHCO₃ aqueous solution. The organiclayer was concentrated under reduced pressure. The residue was purifiedby silica gel chromatography to afford OC-4 (8 mg, 40%).

Preparation of Compound OC-5

To a mixture of 1-methyl-1H-pyrazole (16.4 g, 0.2 mol, 1.0 eq) in dryTHE (150 mL) was added n-BuLi (2.5 M in hexane, 96 mL, 0.24 mol, 1.2 eq)at −78° C. under nitrogen atmosphere. The mixture was stirred at −78° C.for 1 h. Then DMF (30.8 mL, 0.4 mol, 2.0 eq) was added dropwise and themixture was stirred for 1 h. TLC analysis of the reaction mixture showedfull conversion to the desired product. The reaction was quenched with asaturated aqueous solution of NH₄Cl and extracted with EA (3×500 mL).The organic layer was washed with brine and water, dried over Na₂SO₄ andconcentrated under vacuum. The residue was purified by columnchromatography on a silica gel to give compound OI-5a (12.7 g, 58%).

To a mixture of compound OI-5a (2 g, 18.2 mmol, 1.0 eq) in DMF (20 mL)was added NBS (4.86 g, 27.3 mmol, 1.5 eq). The mixture was stirred atroom temperature for 16 h under nitrogen atmosphere. Then the mixturewas filtered and extracted with water and ethyl acetate. The organicphase was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by silica gel chromatography toafford compound OI-5b (2.3 g, 67%).

To a mixture of OI-5b (700 mg, 3.72 mmol, 1.0 eq), 4a-1 (1.27 g, 4.09mmol, 1.1 eq), DPPF (42 mg, 0.503 mmol, 0.1 eq) and DIEA (942 mg, 7.55mmol, 1.5 eq) in toluene (10 mL) was added Pd(dba)₂ (150 mg, 0.260 mmol,0.07 eq) under nitrogen atmosphere. The mixture was stirred at 110° C.for 16 h. Then the mixture was filtered and extracted with water andethyl acetate. The organic phase was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by silicagel chromatography to afford OI-5c (120 mg, 10%)

To a mixture of compound OI-5c (140 mg, 0.414 mmol, 1.0 eq) in MeOH (5mL) was added KCN (54 mg, 0.828 mmol, 2.0 eq) and (NH₄)₂CO₃ (159 mg,1.66 mmol, 4.0 eq). The mixture was stirred at room temperature for 12h. Then the mixture was diluted with water and extracted with ethylacetate. The organic phase was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified byPrep-TLC to give compound OC-5 (67 mg, 40%) as a white solid.

Preparation of Compound OC-6

To a mixture of 4-Imidazolecarboxaldehyde (1 g, 10.4 mmol, 1.0 eq) andNaOAc (14.15 g, 104 mmol, 10 eq) in AcOH (100 mL) was dropwise added asolution of Br₂ (3.8 g, 23.77 mmol, 2.3 eq) in Ac₂O (20 mL) at 0° C.under nitrogen atmosphere. The mixture was stirred at RT for 3 h. TLCanalysis of the reaction mixture showed full conversion to the desiredproduct. The reaction was quenched with saturated NaHCO₃ aqueous andextracted with EA (3×20 mL). The organic layer was washed with brine andwater, dried over Na₂SO₄ and concentrated in vacuum. The residue waspurified by column chromatography to give OI-6a (0.8 g, 44%).

To a mixture of OI-6a (1 g, 5.71 mmol, 1.0 eq) and Cs₂CO₃ (1.86 g, 5.71mmol, 1.0 eq) in DMF (50 mL) was successively added Mel (0.82 g, 5.71mmol, 1.0 eq). The mixture was stirred at RT for 3 h under nitrogenatmosphere. TLC analysis of the reaction mixture showed full conversionto the desired product. Then the mixture was poured into water andextracted with EA (3×30 mL). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by column chromatography on a silicagel to give OI-6b (0.7 g, 65%).

To a mixture of OI-6b (0.7 g, 3.7 mmol, 1.0 eq), 4a-1 (1.27 g, 5.56mmol, 1.5 eq), CyPF-tBu (CAS: 158923-11-6) (21 mg, 0.04 mmol, 0.01 eq)and Cs₂CO₃ (942 mg, 7.55 mmol, 2.5 eq) in DME (10 mL) was added Pd(OAc)₂(8 mg, 0.04 mmol, 0.01 eq) under nitrogen atmosphere. The mixture wasstirred at 110° C. for 16 h. Then the mixture was filtered and extractedwith water and ethyl acetate. The organic phase was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby silica gel chromatography to afford OI-6c (0.28 g, 22%)

To a solution of OI-6c (280 mg, 0.83 mmol, 1.0 eq) in MeOH (5 mL) wasadded (NH₄)₂CO₃ (320 mg, 3.31 mmol, 4.0 eq) and KCN (108 mg, 1.65 mmol,2.0 eq). The mixture was stirred at RT for 16 h. The reaction was addedwith 3 M HCl to adjust pH=1˜2 and stirred at room temperature for 1 h,then a saturated aqueous solution of NaHCO₃ was added to adjust pH=6˜7and extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by silica gel chromatography to giveOC-6 (200 mg, 59%) as a white solid.

Preparation of Compounds OC-7 and OC-10

To a solution of ethyl oxazole-5-carboxylate (0.28 g, 2.00 mmol) inTHF/DMF (2/2 mL) was added Br₂ (0.13 mL, 2.6 mmol, 1.3 eq.) and LHMIDS(2.6 mL 2.6 mmol, 1.3 eq) to obtain a reaction mixture, which wasstirred at −60° C. for 4 hours. The reaction mixture was extracted withEA and water and the combined organic layer was dried with MgSO₄. Theresidue was purified by flash chromatography with EA/Hex (EA/Hex=1:4) togive OS-a.1 as yellow oil (0.1 g, 30%).

To a solution of OS-a.1 (0.3 g, 1.36 mmol) in THE (10 mL) was added NaOH(81 mg, 2.05 mmol, 1.5 eq.) and 4-mercaptophenol (0.17 g, 1.36 mmol, 1eq) was stirred overnight. The reaction mixture was extracted with EAand water and the combined organic layer was dried with MgSO₄. Theresidue was purified by flash chromagraphy with EA/Hex (EA/Hex=1:2) togive OS-a.2 as a yellow solid (0.25 g, 71%).

To a solution of compound OS-a.2 (4.2 g, 15.85 mmol, 1.0 eq) in DMF (40mL) was added 4-(chloromethyl)-2-methylpyridine (2.2 g, 15.85 mmol, 1.0eq) and K₂CO₃ (6.6 g, 47.55 mmol, 3.0 eq) at room temperature undernitrogen atmosphere. The mixture was stirred at 30° C. for 16 h. TLCanalysis of the reaction mixture showed full conversion to the desiredproduct. Then the mixture was diluted with water and extracted withethyl acetate. The organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by silica gel chromatography to afford compound OI-7a (2.5g, 44%).

To a solution of OI-7a (1.4 g, 3.93 mmol, 1.0 eq) in anhydrous THF (10mL) was added DIBAL-H (1 M in hexane, 7.87 mL, 7.87 mmol, 2.0 eq)dropwise at 0° C. The mixture was stirred at 0° C. for 2 h undernitrogen atmosphere. TLC analysis of the reaction mixture showed fullconversion to the desired product. Then the mixture was quenched withsaturated Na₂SO₄·10H₂O solution (50 mL). The mixture was extracted withDCM (3×30 mL). The combined organic phases were washed with brine (2×60mL), dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by silica gel chromatography toafford OI-7b (620 mg, 48%).

To a solution of OI-7b (620 mg, 1.89 mmol, 1.0 eq) in DCM (5 mL) wasadded PDC (1.4 g, 3.78 mmol, 2.0 eq) and K₂CO₃ (782 mg, 5.67 mmol, 3.0eq) at room temperature under nitrogen atmosphere. The mixture wasstirred at 40° C. for 16 h. TLC analysis of the reaction mixture showedfull conversion to the desired product. Then the mixture was dilutedwith water and extracted with DCM. The organic layer was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by silica gel chromatography toafford OI-7c (205 mg, 33%).

To a solution of OI-7c (205 mg, 0.629 mmol, 1.0 eq) in MeOH (3 mL) wasadded (NH₄)₂CO₃ (241 mg, 2.52 mmol, 4.0 eq) and KCN (82 mg, 1.26 mmol,2.0 eq). The mixture was stirred at room temperature for 16 h. Thereaction was added with 3 M HCl to adjust the pH=1 to 2 and stirred atroom temperature for 1 h, then a saturated aqueous solution of NaHCO₃was added to adjust the pH=6 to 7 and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified byprep-TLC to give OC-7 (41 mg, 16%) as a white solid. Compound OC-10 wassynthesized in the same fashion except that(chloromethyl)-2-methylpyridine was replaced with1-(bromomethyl)-3-methylbenzene.

Preparation of Compound OC-8

Compound OC-8 was synthesized by the same procedure as the synthesis ofcompound OC-10 except that the starting material ethyloxazole-5-carboxylate was replaced with ethyl oxazole-4-carboxylate.

Preparation of Compound OC-9

Compound OC-9 was synthesized by the same procedure as the synthesis ofOC-8 except that the starting material 1-(bromomethyl)-3-methylbenzenewas replaced with (3-(bromomethyl)phenyl) methanol.

Preparation of Compound OC-11

Compound OC-11 was synthesized by the same procedure as the synthesis ofOC-8 except that the starting material 1-(bromomethyl)-3-methylbenzenewas replaced with 4-(chloromethyl)-2-methylpyridine.

Preparation of Compound OC-12

To a solution of Bis(4-Hydroxyphenyl)Disulfide (5.0 g, 19.97 mmol, 1.0eq) in DMF (100 mL) was added 4-(chloromethyl)-2-methylpyridine (6.22 g,43.94 mmol, 2.2 eq) and K₂CO₃ (8.2 g, 59.91 mmol, 3 eq). The mixture wasstirred at 45° C. for 12 h. Then the mixture was diluted with water (200mL) and extracted with ethyl acetate (100 mL*3). The organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue was purified by silica gel chromatographyto afford OI-12a (3.9 g, 42%).

To a solution of OI-12a (3.9 g, 8.46 mmol, 1.0 eq) in THF (50 mL) wasadded PPh₃ (2.22 g, 8.46 mmol, 1.0 eq) and concentrated HCl (8.8 mL,84.6 mmol, 10 eq). The mixture was stirred at room temperature for 16 h.Then the mixture was diluted with water (100 mL) and extracted withethyl acetate (50 mL×3). The organic layer was washed with brine, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography to afford compoundOI-12b (2.1 g, 53%).

To a mixture of OI-12b (296 mg, 1.28 mmol, 1.1 eq), OI-5b (220 mg, 1.16mmol, 1.0 eq), DPPF (10 mg, 0.12 mmol, 0.1 eq) and DIEA (225 mg, 1.74mmol, 1.5 eq) in toluene (10 mL) was added Pd₂(dba)₃ (47 mg, 0.08 mmol,0.07 eq) under nitrogen atmosphere. The mixture was stirred at 110° C.for 16 h. Then the mixture was filtered and extracted with water andethyl acetate. The organic phase was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by silicagel chromatography to afford OI-12c (180 mg, 45%)

To a mixture of OI-12c (120 mg, 0.35 mmol, 1.0 eq) in MeOH (4 mL) wasadded KCN (46 mg, 0.7 mmol, 2.0 eq) and (NH₄)₂CO₃ (134 mg, 1.4 mmol, 4.0eq). The mixture was stirred at 45° C. for 16 h. The reaction was added3 M HCl to adjust pH=1˜2 and stirred at room temperature for 1 h, thensaturated aqueous of NaHCO₃ was added to adjust pH=7˜8 and extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by prep-TLC to give compound OC-12 (50 mg, 35%) as a whitesolid.

Preparation of Compound OC-13

To a mixture of OI-6b (310 mg, 1.63 mmol, 1.0 eq), OI-12b (414 mg, 1.79mmol, 1.1 eq), DPPF (88 mg, 0.16 mmol, 0.1 eq) and DIEA (313 mg, 2.43mmol, 1.5 eq) in toluene (16 mL) was added Pd₂(dba)₃ (104 mg, 0.11 mmol,0.07 eq) under nitrogen atmosphere. The mixture was stirred at 110° C.for 16 h. Then the mixture was filtered and extracted with water (50 mL)and ethyl acetate (30 mL×3). The organic phase was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby silica gel chromatography to afford OI-13a (400 mg, 72%)

To a mixture of OI-13a (370 mg, 1.09 mmol, 1.0 eq) in MeOH (10 mL) wasadded KCN (142 mg, 2.18 mmol, 2.0 eq) and (NH₄)₂CO₃ (418 mg, 4.36 mmol,4.0 eq). The mixture was stirred at 45° C. for 16 h. The reaction wasadded with 3 M HCl to adjust pH=1˜2 and stirred at room temperature for1 h, then a saturated aqueous solution of NaHCO₃ was added to adjustpH=7˜8 and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by prep-TLC to give OC-13 (73 mg,16%) as a white solid.

Preparation of Compound OC-14

To a mixture of 4-Imidazolecarboxaldehyde (6 g, 62.44 mmol, 1.0 eq) inTHF (60 mL) was added NaH (3 g, 74.9 mmol, 1.2 eq) at room temperature.After 10 min, the mixture was cooled to −78° C. and Mel (10.5 g, 74.9mmol, 1.2 eq) was added. Then the mixture was gradually warmed to roomtemperature and stirred for 18 h. The reaction was quenched withmethanol (10 mL) and concentrated under reduced pressure. The residuewas purified by silica gel chromatography to afford OI-14a (4 g, 58%).

To a solution of OI-14a (4 g, 36.36 mmol, 1.0 eq) in chloroform (40 mL)was added NBS (7.12 g, 40 mmol, 1.1 eq). The mixture was stirred at 70°C. for 3 h. Then the mixture was cooled to room temperature and dilutedwith a saturated aqueous solution of Na₂CO₃ (50 mL) and DCM (100 mL).The organic layer washed with brine and water, dried over Na₂SO₄ andconcentrated under vacuum. The residue was purified by columnchromatography on silica gel to give OI-14b (333 mg, 4.8%).

To a mixture of OI-14b (333 mg, 1.76 mmol, 1.0 eq), compound OI-12b (448mg, 1.94 mmol, 1.1 eq), DPPF (100 mg, 0.18 mmol, 0.1 eq) and DIEA (340mg, 2.64 mmol, 1.5 eq) in toluene (20 mL) was added Pd₂(dba)₃ (113 mg,0.12 mmol, 0.07 eq) under nitrogen atmosphere. The mixture was stirredat 110° C. for 16 h. Then the mixture was filtered and extracted withwater (50 mL) and ethyl acetate (30 mL×3). The organic phase was driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography to afford OI-14c (261mg, 43%)

To a mixture of OI-14c (261 mg, 0.77 mmol, 1.0 eq) in MeOH (5 mL) wasadded KCN (100 mg, 1.53 mmol, 2.0 eq) and (NH₄)₂CO₃ (295 mg, 3.08 mmol,4.0 eq). The mixture was stirred at 45° C. for 16 h. The reaction wasadded with 3 M HCl to adjust pH=1˜2 and stirred at room temperature for1 h, then a saturated aqueous solution of NaHCO₃ was added to adjustpH=7˜8 and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by prep-TLC to give compound OC-14(183 mg, 58%) as a white solid.

Biological Testing Example 1: MMP Inhibitory Assays

The inhibitory effect of compounds on the rate of cleaving fluorogenicMMP substrate (Enzo, BML-P128) by recombinant human MMP-12 catalyticdomain (Enzo, BML-SE138) was carried out by methods known in the art.Briefly, to each well of a 96-well black opaque plate, all the reagentswere sequentially added by pipetting, and the final reaction contained 4nM of recombinant human MMP-12 catalytic domain, 4 μM of fluorogenic MMPsubstrate, and various concentrations (0.15 nM to 10,000 nM) of testedcompound dilutions in HEPES buffer (pH 7.5) containing 10 mM of CaCl₂,0.01% Brij® 35 (polyoxyethylene (23) lauryl ether), and 0.1 mg/ml ofBSA.

The enzyme and compounds were pre-incubated on a shaker to mix in wells.After an hour of mixing, fluorogenic substrate was added to each well.Reaction without enzyme was used as a blank control in the plate. Theplate was then fed into a plate reader to measure fluorescence intensityat Excitation/Emission wavelengths of 340 nm/440 nm every 10 mins for atleast 1 hour at 37° C. The IC₅₀ of each compound in MMNP-12 inhibitionwas determined by using a readout obtained at time point 30 minutes. Theresults for each compound tested are show in Table 1.

Example 2: Selectivity Assay

The MMP selectivity assay was performed by using other recombinant humanMMPs, including MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10,MMP-13, and MMP-14. The IC₅₀ of the compounds for the other recombinanthuman MPs was determined as described above in Example 1, and are shownin Table 2.

TABLE 2 Selectivity Profile from MMP-12 of Compounds According toEmbodiments of the Application Compound Activity ID MMP-12 MMP-1 MMP-2MMP-3 MMP-7 MMP-8 MMP-9 MM P-10 MMP-13 MMP-14 PC-8  A E D D E E E E D EPC-10 A E D D E D D E D E PC-12 A E D C E D D D E E PC-13 A E D C E D DD D E PC-16 A E C D E D D D D D PC-22 A E D C E D D D C D PC-28 A E D DE C D D C D PC-48 A E D D E D D D C E PC-50 A E C C E C D D C D PC-51 AE D D D C D D C D OC-7  A E C D E C D D C E OC-12 A E C D E C D D C DOC-13 A E C D E C D D C C TC-4  A E D C E C D D D D TC-5  A E D D E D DD E E TC-8  A E C C D B C C B C A = less 10 nM, B = 10 nM to 100 nM, C =100 nM to 1000 nM, D = 1000 nM to 10000 nM, E = greater than 10000 nM

The results in Table 2 above show that compounds according toembodiments of the application have high selectivity for MMP-12 ascompared to other MMPs, including MMP-1 MMP-2, MMP-3, MMP-7, MMP-8,MMP-9, MMP-10, MMP-13, and MMP-14.

Example 3: Efficacy Study of MMP-12 Inhibitors on SD Rat Kidney FibrosisModel by Unilateral Ureteral Occlusion (UUO)

This study was to evaluate the therapeutic efficacy of MMP-12 inhibitor,PC-16 on a renal fibrosis model by unilateral ureteral occlusion (UUO).Male Sprague Dawley (SD) rats (180-220 g, n=71) were used in this study.Animals were randomly divided into 4 groups: vehicle group (group-1,n=8), PC-16 2 mg/kg/day group (group-2, n=9), PC-16 6 mg/kg/day group(group-3, n=10), PC-16 20 mg/kg/day group (group-4, n=9). Animals wereanesthetized with 2.5% isoflurane inhalation. The left ureter wasligated to create a unilateral ureteral occlusion (UUO) model to inducerenal fibrosis. The test article, PC-16 was administrated twice a dayvia oral delivery after modeling for 14 days. Peripheral blood serum wasprepared at pre-modeling and day-15 (one day after last dosing). Allanimals were euthanized and processed for left kidney pathology studies.

PC-16 treatment at dose of 20 mg/kg/day did slightly limit the bloodurea nitrogen (BUN) elevation as compared to vehicle group, however alldata did not show a statistically significant difference as compared tomodel group. Serum creatinine levels did show a similar change as in theBUN.

Histologically, the left kidneys showed significant morphologic changesrelative to the UUO including a pelvic dilatation, renal medulla andcortex atrophy, tubular epithelial cell flattening and tubulardilatation, inflammation and necrosis. Interstitial fibrosis was clearlyobserved in the pelvic wall, medulla and cortex. PC-16 treatment showeda clear dose dependent effect, and a dose at 20 mg/kg/day was moreeffective than a dose of 2 mg/kg/day (p<0.01). The semi-quantitativeevaluation of interstitial inflammation in the cortex indicated asignificant reduction with the treatment of PC-16, and showed a dosedependent efficacy of PC-16. The semi quantitative evaluation ofinterstitial fibrosis in cortex indicated a significant reduction in thefibrosis score with the treatment of PC-16 at all dose groups. There wasa clear dose dependent effect in PC-16 treatment groups.

The analysis of immunohistochemistry (IHC) staining in the cortex areaof the left kidney for the animals treated with PC-16 showed asignificant reduction in collagen-I deposition at a dose of 20 mg/kg/day(P<0.05) with a trance of dose dependent reduction with PC-16 treatment.It also showed a significant reduction in collagen-IV deposition at adose of PC-16 6 mg/kg/day (P<0.05), PC-16 20 mg/kg/day with a trance ofdose dependent reduction with PC-16 treatment.

In conclusion, UUO induced a significant kidney cortex damage,inflammation and interstitial fibrosis within 15 days of modeling. Thetreatment of PC-16 represented a clear dose dependent efficacy either inthe limitation in the kidney damage, interstitial inflammation orinterstitial fibrosis. Fibrosis related biomarker analysis indicated thetreatment with PC-16 reduced the related collagen deposition (Collagen-Iand IV) in the cortex area of damaged kidney.

Detailed Experimental Methods

Animals: Gender: Male, SD rats, 180-220 g, total 71. Certificate:11400700272659, Beijing Vital River Laboratory Animal Technology Co.,Ltd., China. Animal holding: Animals were maintained in atemperature-controlled environment with a 12 hours light/12 hours darkcycle and free access to food and water. Experimental procedures wereperformed according to IACUC guidelines in the KCI (SuZhou) Biotech Inc.(KCI) animal research facility. Model creation: Total 35 male SD ratswere used in this study. After anesthesia with 2.5% isofluraneinhalation the animal abdomen was opened surgically. The left ureter wasexposed and ligated close to the bladder to create the UUO model. Afterconfirming no bleeding, the abdomen wall was closed in layers. Theanimals were maintained under temperature controlled pad (37° C.) forthe recovery from anesthesia, and then were transferred to holding cageswith regular food and water.

Experiment grouping: UUO modeling animals were divided into 7 groupsrandomizedly as vehicle (group-1, n=8), PC-16 2 mg/kg/day (group-5,n=9), PC-16 6 mg/kg/day (group-6, n=10), PC-16 20 mg/kg/day (group-7,n=9) (Table 4.1). Dosing regimen: All test articles were designed as anoral administration via a gastric perfusion. Test articles were designedto be delivered twice a day starting on the same day of modeling for 14days (Table 4.1). Endpoints: 1) Blood collection: Peripheral blood wascollected from all animals in each group and prepared for serum atpre-modeling and day-15 (one day after last dosing), stored at −80° C.All animals were euthanized according to KCI SOP. After confirminganimal death without breath and heart bite the left kidneys wereperfused with cold PBS followed by 10% neutral formalin and collectedfor further pathology study. 2) Detection of serum BUN and creatinine:The serum BUN and creatinine level were detected with Hitachi 7060automatic biochemical analyzer and related test kits. 3) Kidneypathology examination: 3a) Kidney H&E staining and analysis: FollowingKCI's pathologic SOP all left kidneys were fixed in 10% formalin for atleast 24 h at room temperature. After fixation, the kidney was cutlongitudinally to get the largest surface and dehydrated in gradedethanol, cleared in xylene, and embedded in paraffin. Thin sections(3-μm) were mounted on glass slides, dewaxed, rehydrated to distilledwater, and stained with hematoxylin and eosin (H&E). All stained slideswere scanned with NanoZoomer Digital Pathology (S210, Hamamaci, Japan)scanner. Semi quantitative evaluation of the degree of tubularepithelial flattening and dilatation were graded from 0-5 according tothe percentage of tubular involvement: score 0=no damage; score 1=1-10%damage; score 2=10-25% damage; score 3=25-50% damage; score 4=50-75%damage; score 5=75-100% damage. Semi quantitative evaluation of thetubular necrosis is graded from 0 to 3 according to the percentage oftubular involvement: score 0=no necrosis; score 1=<25% necrosis; score2=25-50% necrosis; score 3=>50% necrosis. The average of tubularflattening and dilatation and necrosis as the total tubular damage waspresented. Semi quantitative evaluation of the interstitial inflammationwas graded from 0 to 4 according to the degree of inflammatory cellinfiltration: score 0=no inflammatory cells; score 1=mild inflammatorycell infiltration; score 2=moderate inflammatory cell infiltration;score 3=severe inflammatory cell infiltration; score 4=extensiveinflammatory cell infiltration. 3b) Kidney Masson Trichrome staining andanalysis: Thin sections (3-μm) were mounted on glass slides, dewaxed,rehydrated to distilled water, and stained with Masson Trichrome. Allstained slides were scanned with NanoZoomer Digital Pathology (S210,Hamamaci, Japan) scanner. Semi quantitative evaluation of cortexinterstitial fibrosis with five different fields at ×10 magnificationare selected randomly from kidney cortex, estimated using the followingscoring system from 0-4 according to the percentage of interstitialfibrosis involvement: score 0=no fibrosis; score 1=<10% fibrosis; score2=10-25% fibrosis; score 3=25-75% fibrosis; score 4=>75% fibrosis. 3c)Kidney IHC staining and analysis: All of left kidneys from each group(eight right kidneys from model group) were processed for biomarkeranalysis using IHC methods, such as Collagen-I (Abcam, Cat #ab34710),Collagen-IV (Abcam, Cat #ab6586). The IHC staining was processedaccording to the standard protocol of IHC at KCI. The stained slideswere then scanned by Hamamatsu NanoZoomer Digital Pathology S210 slidescanner and analyzed using the software to get the positive stainingarea/analysis area (%). 4) Statistical analysis: Graphpad, prism 5.0 wasused for all statistical analyses with p value <0.05 consideredsignificant. All data were reported as mean±SEM. Differences betweengroups were determined using either ANOVA tests with Bonferroni test orstudent T-test.

TABLE 4.1 Aninal Experiment Groups Conc. Dosage Dosage Group N OP CPDMg/mL mL/kg mg/kg Group-1 9 UUO Vehicle N/A 10 N/A Group-2 9 UUO PC-160.1 mg/ml 10  2 mg/kg/d, bid Gronp-3 9 UUO PC-16 0.3 mg/ml 10  6mg/kg/d, bid Group-4 9 UUO PC-16   1 mg/ml 10 20 mg/kg/d, bid

Results:

-   -   a) Animal physiological changes during the experimental periods:        Several animals died during the experimental period, which was        considered as the model failed such as the ureter ruptured        during the operation, which induced peritonitis. The numbers of        animals died in each group was showed in Table 4.1.    -   b) Changes in the serum BUN and creatitine: Serum BUN in all        animals was raised after UUO at day-15 as compared to the pre        modeling (p<0.001). PC-16 treatment at a dose of 20 mg/kg/day        showed the same result (FIG. 1A); all data did not show a        statistically significant difference as compared to model group.        Serum creatinine levels did show a similar change as in the BUN        (FIG. 1 ).    -   c) Changes in the left kidney damage—The tubular damages: After        15 days of UUO, the left kidney showed pelvic cavity dilatation        in all animals. The kidney cortex represented a significant        atrophy with different degree of tubular epithelial cell        flattening, tubular dilatation and interstitial inflammatory        cell infiltration, and few foci of tubular necrosis (FIG. 1C).        PC-16 treatment represented a clear dose dependent effect, and a        dose at 20 mg/kg/day was more effect than a dose of 2 mg/kg/day        (p<0.01) (FIG. 1D (I)).    -   d) Changes in the left kidney damage—The interstitial        inflammation: The semi quantitative evaluation of interstitial        inflammation in cortex indicated a significant reduction with        the treatment of PC-16, and presented a dose dependent efficacy        of PC-16 (FIG. 1D (II)).    -   e) Changes in the left kidney damage—The cortex interstitial        fibrosis: After 15 days of UUO, the left kidney showed pelvic        cavity, medulla area and cortex area with a significant        interstitial fibrosis in all animals. The interstitial fibrosis        in the cortex area was analyzed and represented a different        degree with the test CPDs' treatment (FIG. 1E). The semi        quantitative evaluation of interstitial fibrosis in cortex        indicated a significant reduction in the fibrosis score with the        treatment of PC-16 at dose of 20 mg/kg/day (p<0.001). There was        a clear dose dependent effect in PC-16 treatment groups (FIG.        1F).    -   f) Pathological analysis of multiple biomarkers in left kidney:        Collagen-I: The analysis of IHC staining in the cortex area of        left kidney for the animals treated with PC-16 showed a        significant reduction in collagen-I deposition at a dose of 20        mg/kg/day (p<0.05); a trance of dose dependent reduction in        PC-16 treatment groups (FIG. 1G(I) and FIG. 1H(I)). Collagen-IV:        IHC staining in the cortex area of the left kidney for the        animals treated with PC-16 showed a significant reduction in        collagen-IV deposition at dose of 20 mg/kg/day (p<0.05); a        trance of dose dependent reduction with PC-16 treatment (FIG.        1G(II) and FIG. 1H(II)).

REFERENCES

-   1. U.S. Pat. No. 7,179,831-   2. WO 02/096426-   3. US 2004/0067996-   4. WO 2004/108086-   5. WO 02/074752-   6. WO 2004/020415

1. A compound of formula (I):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof, wherein: ring B is an optionally substituted aryl oroptionally substituted heteroaryl; ring C is aryl or heteroaryl; ring Dis aryl or heteroaryl; each of X, Y, and Z is independently selectedfrom the group consisting of O, CH₂, NR_(x), and S(O)_(q), wherein R_(x)is hydrogen or alkyl; R₁ is hydrogen or alkyl; each R₂ is independentlyselected from the group consisting of hydrogen, alkyl, halo, hydroxyl,haloalkyl, alkoxy, alkylthio, amino, amide, alkylamine, aminoalkyl,cyano, hydroxyalkyl, —(CH₂)_(p)C(O)OR₆, and —(CH₂)_(p)OC(O)R₆; each R₃is independently selected from the group consisting of hydrogen, alkyland halo; R₄ is hydrogen or alkyl; R₅ is hydrogen; each R₆ isindependently selected from the group consisting of hydrogen and alkyl,wherein the alkyl is unsubstituted or substituted with one or moregroups independently selected from the group consisting of amino,hydroxyl, halo, and alkoxy; m is 1, 2, 3, or 4; n is 1, 2, 3, 4, or 5; pis 0, 1, 2, 3, 4, or 5; and q is 0, 1, or 2, provided that ring B is notfuranyl.
 2. The compound of claim 1, wherein ring C is phenyl.
 3. Thecompound of claim 1, wherein ring D is pyridinyl or phenyl.
 4. Thecompound of claim 1, wherein ring D is:


5. The compound of claim 1, wherein each of R₁, R₄ and R₅ is hydrogen.6. The compound of claim 1, wherein X is S; Y is O; and Z is CH₂.
 7. Thecompound of claim 1, wherein ring B is a five or six membered monocyclicheteroaryl having 1-2 heteroatoms independently selected from N, S, andO, wherein the five or six membered monocyclic heteroaryl is optionallysubstituted with —CH₃.
 8. The compound of claim 7, wherein ring B ispyridinyl, thiophenyl, imidazolyl, pyrazolyl, or oxazolyl, wherein eachof pyridinyl, thiophenyl, imidazolyl, pyrazolyl, and oxazolyl isoptionally substituted with —CH₃.
 9. The compound of claim 7, whereinring B is pyridinyl.
 10. The compound of claim 9, wherein the compoundis selected from the group consisting of a compound of formula (II-a), acompound of formula (II-b), a compound of formula (II-c), and a compoundof formula (II-d):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof, wherein: R₁ is hydrogen, —CH₃, or —CH₂CH₃; R₄ ishydrogen or —CH₃; R₅ is hydrogen or —CH₃; R₃ is hydrogen, —F, —Cl, orCH₃; X is S, SO, or SO₂; Y is O, NH, CH₂, or NHCH₃; ring D is pyridinylor phenyl; R₂ is —CH₃, —CH₂OH, —OH, CH₂OC(O)CH(NH₂)CH(CH₃)₂, —COOH,—C(O)NH₂, —C(O)NHCH₃, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂, or —CH₂CH(CH₃)₂; andn is 0 or
 1. 11. The compound of claim 7, wherein ring B is thiophenyl.12. The compound of claim 11, wherein the compound is a compound offormula (IV):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof, wherein: each of R₁, R₄ and R₅ is hydrogen; X is S; Yis O; R₃ is hydrogen; ring D is phenyl or pyridinyl; R₂ is —CH₃,—C(O)NH₂, —CH₂OH, —OCH₃, or —OH; and n is 0 or
 1. 13. The compound ofclaim 7, wherein the compound is selected from the group consisting of acompound of formula (Va), a compound of formula (Vb) and a compound offormula (VI):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof, wherein: each of R₁, R₃, R₄, and R₅ is hydrogen; X isS; Y is O; ring D is phenyl or pyridinyl; R₂ is —CH₃, —C(O)NH₂, —CH₂OH,—OCH₃, or —OH; and n is 0 or
 1. 14. The compound of claim 7, wherein thecompound is selected from the group consisting of a compound of formula(VII-a) and a compound of formula (VII-b):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof, wherein: each of R₁, R₃, R₄, and R₅ is hydrogen; X isS; Y is O; ring D is phenyl or pyridinyl; R₂ is —CH₃, —C(O)NH₂, —CH₂OH,—OCH₃, or —OH; and n is 0 or
 1. 15. The compound of claim 1 being acompound of formula (I-a):

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof, wherein: ring B is pyridinyl; Q is CH or N; R₁ ishydrogen, —CH₃, or —CH₂CH₃; R₄ is hydrogen or —CH₃; R₅ is hydrogen or—CH₃; R₂ is selected from the group consisting of —CH₃, —C(O)NH₂,—CH₂OH, —OCH₃, or —OH; X is S; and Y is O.
 16. The compound of claim 15,wherein each of R₁, R₄, and R₅ is hydrogen.
 17. A compound selected fromthe group consisting of:

or a tautomer, stereoisomer, pharmaceutically acceptable salt, orsolvate thereof.
 18. The compound of claim 17, or a pharmaceuticallyacceptable salt thereof.
 19. A pharmaceutical composition comprising thecompound of claim 1, and at least one pharmaceutically acceptablecarrier.
 20. A method of inhibiting macrophage elastase (MMP-12) in asubject in need thereof, the method comprising administering to thesubject the pharmaceutical composition of claim
 19. 21. A method oftreating a disease mediated by macrophage elastase (MMP-12) in a subjectin need thereof, the method comprising administering to the subject thepharmaceutical composition of claim 19, wherein the disease is selectedfrom the group consisting of asthma, chronic obstructive pulmonarydisease (COPD), a emphysema, acute lung injury, idiopathic pulmonaryfibrosis (IPF), sarcoidosis, systemic sclerosis, liver fibrosis,nonalcoholic steatohepatitis (NASH), arthritis, cancer, heart disease,inflammatory bowel disease (IBD), acute kidney injury (AKI), chronickidney disease (CKD), Alport syndrome, and nephritis.